Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer's Disease. - Basha, Sk Chand; Ramaiah, Mekala Janaki; Kosagisharaf, Jagannatha Rao (J Alzheimers Dis, 2023)
Alzheimer's disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-β (Aβ), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aβ is one of the physiological roles of TREM2, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by impairing TREM2-Aβ binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aβ phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aβ clearance. We indicate that TREM2 has the potential to ameliorate the Aβ burden, though with differential clearance ability and may act as a potential therapeutic target.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Humans; Membrane Glycoproteins; Microglia; Neurons; Receptors, Immunologic

Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia. - Yoshida, Madoka; Uemura, Takeshi; Mizoi, Mutsumi; Waragai, Masaaki; Sakamoto, Akihiko; Terui, Yusuke; Kashiwagi, Keiko; Igarashi, Kazuei (J Alzheimers Dis, 2023)
BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL). OBJECTIVE: In this study, we sought novel biomarkers for dementia in urine. METHODS: Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using N ɛ -(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit. RESULTS: We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively. CONCLUSION: Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness.

Vacuolar Protein-Sorting Proteins Are Reduced Even Before Cognitive Decline in a Mouse Model of Alzheimer's Disease. - Shinagawa, Hijiri; Ohuchi, Kazuki; Goto, Yuya; Hashimoto, Kohei; Kijima, Hideki; Maekawa, Shogo; Kurita, Hisaka; Inden, Masatoshi (J Alzheimers Dis, 2023)
Currently, interventions from the preclinical stage are considered necessary for the treatment of Alzheimer's disease (AD). Previous studies have reported that vacuolar protein-sorting protein (VPS), a retromer construct, is involved in the pathogenic mechanisms of AD and Parkinson's disease. This study evaluated VPS26, VPS29, and VPS35 before and after the onset of cognitive decline in an App knock-in mouse model of AD that more closely resembles the human pathology than previous AD models. The results showed that the expression of VPS26 and VPS35 decreased before the onset of cognitive decline, suggesting the possibility of anti-amyloid-β disease-modifying treatment targeting these proteins.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Humans; Mice; Protein Transport; Vesicular Transport Proteins

Validation of a Multivariate Prediction Model of the Clinical Progression of Alzheimer's Disease in a Community-Dwelling Multiethnic Cohort. - Stallard, Eric; Kociolek, Anton; Jin, Zhezhen; Ryu, Hyunnam; Lee, Seonjoo; Cosentino, Stephanie; Zhu, Carolyn; Gu, Yian; Fernandez, Kayri; Hernandez, Michelle; Kinosian, Bruce; Stern, Yaakov (J Alzheimers Dis, 2023)
BACKGROUND: The major aims of the three Predictors Studies have been to further our understanding of Alzheimer's disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD. OBJECTIVES: To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI). METHODS: The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm. RESULTS: Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer's centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up. CONCLUSION: These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time.

3-Hydroxyacyl-CoA and Alcohol Dehydrogenase Activities of Mitochondrial Type 10 17β-Hydroxysteroid Dehydrogenase in Neurodegeneration Study. - He, Xue-Ying; Dobkin, Carl; Brown, W Ted; Yang, Song-Yu (J Alzheimers Dis, 2022)
BACKGROUND: Mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aβ-peptide binding alcohol dehydrogenase (ABAD), formerly endoplasmic reticulum-associated Aβ-peptide binding protein (ERAB), for two decades so long as ABAD serves as the alternative term of 17β-HSD10. OBJECTIVE: To determine whether those ABAD reports are true or false, even if they were published in prestigious journals. METHODS: 6xHis-tagged 17β-HSD10 was prepared and characterized by well-established experimental procedures. RESULTS: The N-terminal 6xHis tag did not significantly interfere with the dehydrogenase activities of 17β-HSD10, but the kinetic constants of its 3-hydroxyacyl-CoA dehydrogenase activity are drastically distinct from those of ABAD, and it was not involved in ketone body metabolism as previously reported for ABAD. Furthermore, it was impossible to measure its generalized alcohol dehydrogenase activities underlying the concept of ABAD because the experimental procedures described in ABAD reports violated basic chemical and/or biochemical principles. More incredibly, both authors and journals had not yet agreed to make any corrigenda of ABAD reports. CONCLUSION: Brain 17β-HSD10 plays a key role in neurosteroid metabolism and further studies in this area may lead to potential treatments of neurodegeneration including AD.

5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer's Disease. - Chen, Lei; Shen, Qianqian; Xu, Shunliang; Yu, Hongzhuan; Pei, Shengjie; Zhang, Yangting; He, Xin; Wang, QiuZhen; Li, Duo (J Alzheimers Dis, 2022)
BACKGROUND: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer's disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. OBJECTIVE: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date. METHODS: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control. RESULTS: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects. CONCLUSION: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.
Keywords: 5-Methylcytosine; Aged; Alzheimer Disease; Biomarkers; Case-Control Studies; Cell-Free Nucleic Acids; DNA Methylation; DNA, Neoplasm; Epigenesis, Genetic; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer's Disease Mouse Model. - Pontrello, Crystal G; McWhirt, Joshua M; Glabe, Charles G; Brewer, Gregory J (J Alzheimers Dis, 2022)
BACKGROUND: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD). OBJECTIVE: To profile the progression of pathology in AD. METHODS: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. RESULTS: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. CONCLUSION: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by an pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

Alteration of Gut Microbiota in Alzheimer's Disease and Their Relation to the Cognitive Impairment. - Khedr, Eman M; Omeran, Nehad; Karam-Allah Ramadan, Haidi; Ahmed, Gellan K; Abdelwarith, Ahmed M (J Alzheimers Dis, 2022)
BACKGROUND: Dysbiosis of gut microbiota has been reported to be enrolled in the pathogenesis of Alzheimer's disease (AD). However, there is a lack of relevant studies on this topic in Egyptian patients with AD. OBJECTIVE: To investigate different species of gut microbiota in Egyptian patients with AD and correlate microbiota bacterial abundance with clinical data. METHODS: The study included 25 patients with AD and 25 healthy volunteers as age and sex-matched controls. Clinical data was taken for each patient, including medical history and examination; Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were assessed for each participant. Bacterial DNA was extracted from stool, and abundance quantified via qPCR using 16S rRNA group-specific primers. RESULTS: Akkermansia, Enterobacteria, Bacteroidetes, Bacillus cereus, Prevotella, and Clostridium cluster IV were more abundant in the AD group than in the control group, although there was significantly less abundance of Bifidobacterium spp., Firmicutes, and Actinobacteria in patients with AD than in controls, whereas no such significance was found for lactic acid bacteria between both groups. Lactic acid bacteria and Prevotella abundance was negatively correlated with cognitive impairment (p = 0.03 with MMSE, and p = 0.03 with MoCA). Prevotella abundance was positively correlated with age of onset and duration of illness and negatively correlated with smoking and coronary heart disease (p = 0.007, p = 0.03, p = 0.035, and p = 0.047, respectively). CONCLUSION: The current work highlighted a significant relationship between AD and gut microbiota dysbiosis. A higher abundance of Prevotella species and lactic acid bacteria was correlated with cognition.
Keywords: Alzheimer Disease; Bacteria; Cognitive Dysfunction; Dysbiosis; Gastrointestinal Microbiome; Humans; RNA, Ribosomal, 16S

Alzheimer's Disease Diagnostics Using miRNA Biomarkers and Machine Learning. - Xu, Amy; Kouznetsova, Valentina L; Tsigelny, Igor F (J Alzheimers Dis, 2022)
BACKGROUND: The current standard for Alzheimer's disease (AD) diagnosis is often imprecise, as with memory tests, and invasive or expensive, as with brain scans. However, the dysregulation patterns of miRNA in blood hold potential as useful biomarkers for the non-invasive diagnosis and even treatment of AD. OBJECTIVE: The goal of this research is to elucidate new miRNA biomarkers and create a machine-learning (ML) model for the diagnosis of AD. METHODS: We utilized pathways and target gene networks related to confirmed miRNA biomarkers in AD diagnosis and created multiple models to use for diagnostics based on the significant differences among miRNA expression between blood profiles (serum and plasma). RESULTS: The best performing serum-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 92.0% accuracy and the best performing plasma-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 90.9% accuracy. Through analysis of AD implicated miRNA, thousands of descriptors reliant on target gene and pathways were created which can then be used to identify novel biomarkers and strengthen disease diagnosis. CONCLUSION: Development of a ML model including miRNA and their genomic and pathway descriptors made it possible to achieve considerable accuracy for the prediction of AD.

Alzheimer's Disease: Key Insights from Two Decades of Clinical Trial Failures. - Kim, C Kwon; Lee, Yin Rui; Ong, Lynnett; Gold, Michael; Kalali, Amir; Sarkar, Joydeep (J Alzheimers Dis, 2022)
Given the acknowledged lack of success in Alzheimer's disease (AD) drug development over the past two decades, the objective of this review was to derive key insights from the myriad failures to inform future drug development. A systematic and exhaustive review was performed on all failed AD compounds for dementia (interventional phase II and III clinical trials from ClinicalTrials.gov) from 2004 to the present. Starting with the initial ∼2,700 AD clinical trials, ∼550 trials met our initial criteria, from which 98 unique phase II and III compounds with various mechanisms of action met our criteria of a failed compound. The two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved. Potential contributing methodological factors for the clinical trial failures were categorized into 1) insufficient evidence to initiate the pivotal trials, and 2) pivotal trial design shortcomings. Our evaluation found that rational drug development principles were not always followed for AD therapeutics development, and the question remains whether some of the failed compounds may have shown efficacy if the principles were better adhered to. Several recommendations are made for future AD therapeutic development. The whole database of the 98 failed compounds is presented in the Supplementary Material.
Keywords: Alzheimer Disease; Humans

Alzheimer's Disease with Epileptiform EEG Activity: Abnormal Cortical Sources of Resting State Delta Rhythms in Patients with Amnesic Mild Cognitive Impairment. - Babiloni, Claudio; Noce, Giuseppe; Di Bonaventura, Carlo; Lizio, Roberta; Eldellaa, Ali; Tucci, Federico; Salamone, Enrico M; Ferri, Raffaele; Soricelli, Andrea; Nobili, Flavio; Famá, Francesco; Arnaldi, Dario; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Patients with amnesic mild cognitive impairment due to Alzheimer's disease (ADMCI) typically show a "slowing" of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that "slowing." OBJECTIVE: Here we tested the hypothesis that the "slowing" of rsEEG rhythms is related to EEA in ADMCI patients. METHODS: Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals. RESULTS: EEA was observed in 15% (N = 8) of the ADMCI patients. The ADMCI-EEA group showed: 1) more abnormal Aβ 42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta ( CONCLUSION: It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance.

Analysis and Identification Genetic Effect of SARS-CoV-2 Infections to Alzheimer's Disease Patients by Integrated Bioinformatics. - Wang, Fang; Xu, Jia; Xu, Shu-Jun; Guo, Jie-Jie; Wang, Feiming; Wang, Qin-Wen (J Alzheimers Dis, 2022)
BACKGROUND: COVID-19 pandemic is a global crisis which results in millions of deaths and causes long-term neurological sequelae, such as Alzheimer's disease (AD). OBJECTIVE: We aimed to explore the interaction between COVID-19 and AD by integrating bioinformatics to find the biomarkers which lead to AD occurrence and development with COVID-19 and provide early intervention. METHODS: The differential expressed genes (DEGs) were found by GSE147507 and GSE132903, respectively. The common genes between COVID-19 and AD were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interactions (PPI) network analysis were carried out. Hub genes were found by cytoscape. A multivariate logistic regression model was constructed. NetworkAnalyst was used for the analysis of TF-gene interactions, TF-miRNA coregulatory network, and Protein-chemical Interactions. RESULTS: Forty common DEGs for AD and COVID-19 were found. GO and KEGG analysis indicated that the DEGs were enriched in the calcium signal pathway and other pathways. A PPI network was constructed, and 5 hub genes were identified (ITPR1, ITPR3, ITPKB, RAPGEF3, MFGE8). Four hub genes (ITPR1, ITPR3, ITPKB, RAPGEF3) which were considered as important factors in the development of AD that were affected by COVID-19 were shown by nomogram. Utilizing NetworkAnalyst, the interaction network of 4 hub genes and TF, miRNA, common AD risk genes, and known compounds is displayed, respectively. CONCLUSION: COVID-19 patients are at high risk of developing AD. Vaccination is required. Four hub genes can be considered as biomarkers for prediction and treatment of AD development caused by COVID-19. Compounds with neuroprotective effects can be used as adjuvant therapy for COVID-19 patients.
Keywords: Alzheimer Disease; Computational Biology; COVID-19; Databases, Genetic; Gene Expression Profiling; Humans; Protein Interaction Maps; SARS-CoV-2

Anticholinergic Drug Burden and Neurocognitive Performance in the Study of Latinos-Investigation of Neurocognitive Aging. - Posis, Alexander Ivan B; Tarraf, Wassim; Gonzalez, Kevin A; Soria-Lopez, Jose A; Léger, Gabriel C; Stickel, Ariana M; Daviglus, Martha L; Lamar, Melissa; Zeng, Donglin; González, Hector M (J Alzheimers Dis, 2022)
BACKGROUND: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos. OBJECTIVE: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos. METHODS: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (n = 6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change. RESULTS: Anticholinergic use was associated with lower cognitive global cognition (β= -0.21; 95% CI [-0.36; -0.05]), learning (β= -0.27; 95% CI [-0.47; -0.07]), memory (β= -0.22; 95% CI [-0.41; -0.03]), and executive functioning (β= -0.22; 95% CI [-0.40; -0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (β: -0.28 [95% CI: -0.55, -0.01]; β: -0.28 [95% CI: -0.55, -0.01]; β: -0.25, [95% CI -0.47, -0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F3 = 3.59, F3 = 2.84, F3 = 3.88, respectively). CONCLUSION: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact.

Antihypertensive Medication Class and the Risk of Dementia and Cognitive Decline in Older Adults: A Secondary Analysis of the Prospective HELIAD Cohort. - Liampas, Ioannis; Hatzimanolis, Alex; Siokas, Vasileios; Yannakoulia, Mary; Kosmidis, Mary H; Sakka, Paraskevi; Hadjigeorgiou, Georgios M; Scarmeas, Nikolaos; Dardiotis, Efthimios (J Alzheimers Dis, 2022)
BACKGROUND: It is unclear whether the main antihypertensive medication classes (diuretics, calcium channel blockers, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers (ARBs)) are associated with different risks of cognitive decline. Published evidence is conflicting and stems mainly from observational studies. OBJECTIVE: To investigate the differential effects of antihypertensives on the risks of developing dementia and cognitive decline, with a specific focus on the vascular component of the mechanisms underlying these interactions. METHODS: Older adults with a history of hypertension and without dementia were drawn from the population-based HELIAD cohort. Age-, gender-, education-, and antihypertensive medication- (five dichotomous exposures) adjusted Cox proportional-hazards models and generalized estimating equations were performed to appraise the associations of baseline antihypertensive therapy with dementia incidence and cognitive decline (quantified using a comprehensive neuropsychological battery). Analyses were subsequently adjusted for clinical vascular risk (dyslipidemia, diabetes mellitus, smoking, cardiovascular, and cerebrovascular history) and genetic susceptibility to stroke (using polygenic risk scores generated according to the MEGASTROKE consortium GWAS findings). RESULTS: A total of 776 predominantly female participants (73.61±4.94 years) with hypertension and a mean follow-up of 3.02±0.82 years were analyzed. Baseline treatment was not associated with the risk of incident dementia. ARB users experienced a slower yearly global cognitive [2.5% of a SD, 95% CI = (0.1, 4.9)] and language [4.4% of a SD, 95% CI = (1.4, 7.4)] decline compared to non-users. The fully adjusted model reproduced similar associations for both global cognitive [β= 0.027, 95% CI =  (-0.003, 0.057)], and language decline [β= 0.063, 95% CI = (0.023, 0.104)]. CONCLUSION: ARBs may be superior to other antihypertensive agents in the preservation of cognition, an association probably mediated by vascular-independent mechanisms.
Keywords: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cognitive Dysfunction; Dementia; Diuretics; Female; Humans; Hypertension; Male; Prospective Studies

Anti-Inflammatory Gene Therapy Improves Spatial Memory Performance in a Mouse Model of Alzheimer's Disease. - Yoo, Tai June (J Alzheimers Dis, 2022)
The immune system plays a critical role in neurodegenerative processes involved in Alzheimer's disease (AD). In this study, a gene-based immunotherapeutic method examined the effects of anti-inflammatory cellular immune response elements (CIREs) in the amyloid-β protein precursor (AβPP) mouse model. Bi-monthly intramuscular administration, beginning at either 4 or 6 months, and examined at 7.5 through 16 months, with plasmids encoding Interleukin (IL)-10, IL-4, TGF-β polynucleotides, or a combination thereof, into AβPP mice improved spatial memory performance. This work demonstrates an efficient gene therapy strategy to downregulate neuroinflammation, and possibly prevent or delay cognitive decline in AD.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Cognition; Disease Models, Animal; Female; Genetic Therapy; Immunity, Cellular; Immunotherapy; Injections, Intramuscular; Interleukin-10; Interleukin-4; Male; Mice; Mice, Transgenic; Spatial Memory

APOEɛ4 Allele Moderates the Association Between Basal Forebrain Nuclei Volumes and Allocentric Navigation in Older Adults Without Dementia. - Lerch, Ondřej; Pařízková, Martina; Vyhnálek, Martin; Nedelska, Zuzana; Hort, Jakub; Laczó, Jan (J Alzheimers Dis, 2022)
BACKGROUND: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer's disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOEɛ4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. OBJECTIVE: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they operate on aSN through MTL and PFC or independently from these structures. METHODS: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). RESULTS: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1 - 2 = 0.039; pch4p = 0.042) and PFC (pch4ai = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p = 0.035). CONCLUSION: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations.

Association Between High Serum Tetrahydrofolate and Low Cognitive Functions in the United States: A Cross-Sectional Study. - Fan, Yaohua; Liu, Wen; Chen, Si; Li, Mengzhu; Zhao, Lijun; Wu, Chunxiao; Liu, Helu; Zhu, Meiling (J Alzheimers Dis, 2022)
BACKGROUND: The relationship between serum folate status and cognitive functions is still controversial. OBJECTIVE: To evaluate the association between serum tetrahydrofolate and cognitive functions. METHODS: A total of 3,132 participants (60-80 years old) from the 2011-2014 NHANES were included in this cross-sectional study. The primary outcome measure was cognitive function assessment, determined by the Consortium to Establish a Registry for Alzheimer's Disease Word Learning Test (CERAD-WL), CERAD-Delayed Recall Test (CERAD-DR), Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), and global cognitive score. Generalized linear model (GLM), multivariate logistic regression models, weighted generalized additive models (GAM), and subgroup analyses were performed to evaluate the association between serum tetrahydrofolate and low cognitive functions. RESULTS: In GLM, and the crude model, model 1, model 2 of multivariate logistic regression models, increased serum tetrahydrofolate was associated with reduced cognitive functions via AF, DSST, CERAD-WL, CERAD-DR, and global cognitive score (p <  0.05). In GAM, the inflection points were 1.1, 2.8, and 2.8 nmol/L tetrahydrofolate, determined by a two-piece wise linear regression model of AF, DSST, and global cognitive score, respectively. Also, in GAM, there were no non-linear relationship between serum tetrahydrofolate and low cognitive functions, as determined by CERAD-WL or CERAD-DR. The results of subgroup analyses found that serum tetrahydrofolate levels and reduced cognitive functions as determined by AF had significant interactions for age and body mass index. The association between high serum tetrahydrofolate level and reduced cognitive functions as determined using DSST, CERAD-WL, CERAD-DR, or global cognitive score had no interaction with the associations between cognition and gender, or age, or so on. CONCLUSION: High serum tetrahydrofolate level is associated with significantly reduced cognitive function.

Association Between Plasma Biomarkers of Amyloid, Tau, and Neurodegeneration with Cerebral Microbleeds. - McCarter, Stuart J; Lesnick, Timothy G; Lowe, Val J; Rabinstein, Alejandro A; Przybelski, Scott A; Algeciras-Schimnich, Alicia; Ramanan, Vijay K; Jack, Clifford R; Petersen, Ronald C; Knopman, David S; Boeve, Bradley F; Kantarci, Kejal; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. OBJECTIVE: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. METHODS: 712 participants from the Mayo Clinic Study of Aging with T2 * GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. RESULTS: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8-116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC -53.0). CONCLUSION: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population. - Liu, Xi-Xi; Wu, Peng-Fei; Liu, Ying-Zi; Jiang, Ya-Ling; Wan, Mei-Dan; Xiao, Xue-Wen; Yang, Qi-Jie; Jiao, Bin; Liao, Xin-Xin; Wang, Jun-Ling; Liu, Shao-Hui; Zhang, Xuewei; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Alzheimer's disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. OBJECTIVE: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. METHODS: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. RESULTS: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. CONCLUSION: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Case-Control Studies; China; Female; Folic Acid; Humans; Logistic Models; Male; Mental Status and Dementia Tests; Middle Aged; Riboflavin; Risk; Vitamin B 12; Vitamin D; Vitamin E

Association of Alzheimer's Disease with COVID-19 Susceptibility and Severe Complications: A Nationwide Cohort Study. - Chung, Seok Jong; Chang, Yoonkyung; Jeon, Jimin; Shin, Jae Il; Song, Tae-Jin; Kim, Jinkwon (J Alzheimers Dis, 2022)
BACKGROUND: Identification of patients at high susceptibility and high risk of developing serious complications related to coronavirus disease 2019 (COVID-19) infection is clinically important in the face of the COVID-19 pandemic. OBJECTIVE: To investigate whether patients with Alzheimer's disease (AD) are more susceptible to COVID-19 infection and whether they have a higher risk of developing serious complications. METHODS: We retrospectively reviewed the Korean nationwide population-based COVID-19 dataset for participants who underwent real-time reverse transcription polymerase chain reaction assays for COVID-19 between January 1 and June 4, 2020. A 1 : 3 ratio propensity score matching and binary logistic regression analysis were performed to investigate the association between AD and the susceptibility or severe complications (i.e., mechanical ventilation, intensive care unit admission, or death) of COVID-19. RESULTS: Among 195,643 study participants, 5,725 participants had AD and 7,334 participants were diagnosed with COVID-19. The prevalence of participants testing positive for COVID-19 did not differ according to the presence of AD (p = 0.234). Meanwhile, AD was associated with an increased risk of severe COVID-19 complications (OR 2.25 [95% CI 1.54-3.28]). Secondary outcome analyses showed that AD patients had an increased risk for mortality (OR 3.09 [95% CI 2.00-4.78]) but were less likely to receive mechanical ventilation (OR 0.42 [95% CI 0.20-0.87]). CONCLUSION: AD was not associated with increased susceptibility to COVID-19 infection, but was associated with severe COVID-19 complications, especially with mortality. Early diagnosis and active intervention are necessary for patients with AD suspected COVID-19 infection.
Keywords: Alzheimer Disease; Cohort Studies; COVID-19; Humans; Pandemics; Retrospective Studies; SARS-CoV-2

Association of Aspirin Use with Reduced Risk of Developing Alzheimer's Disease in Elderly Ischemic Stroke Patients: A Retrospective Cohort Study. - Gorenflo, Maria P; Davis, Pamela B; Kendall, Ellen K; Olaker, Veronica R; Kaelber, David C; Xu, Rong (J Alzheimers Dis, 2022)
BACKGROUND: Currently there are no effective therapies to prevent or halt the development of Alzheimer's disease (AD). Multiple risk factors are involved in AD, including ischemic stroke (IS). Aspirin is often prescribed following IS to prevent blood clot formation. Observational studies have shown inconsistent findings with respect to the relationship between aspirin use and the risk of AD. OBJECTIVE: To investigate the relationship between aspirin therapy after IS and the new diagnosis of AD in elderly patients. METHODS: This retrospective cohort study leveraged a large database that contains over 90 million electronic health records to compare the hazard rates of AD after IS in elderly patients prescribed aspirin versus those not prescribed aspirin after propensity-score matching for relevant confounders. RESULTS: At 1, 3, and 5 years after first IS, elderly patients prescribed aspirin were less likely to develop AD than those not prescribed aspirin: Hazard Ratio = 0.78 [0.65,0.94], 0.8 1 [0.70,0.94], and 0.76 [0.70,0.92]. CONCLUSION: Our findings suggest that aspirin use may prevent AD in patients with IS, a subpopulation at high risk of developing the disease.

Association of Brain Volume and Retinal Thickness in the Early Stages of Alzheimer's Disease. - Mathew, Sunu; WuDunn, Darrell; Mackay, Devin D; Vosmeier, Aaron; Tallman, Eileen F; Deardorff, Rachael; Harris, Alon; Farlow, Martin R; Brosch, Jared R; Gao, Sujuan; Apostolova, Liana G; Saykin, Andrew J; et al. (J Alzheimers Dis, 2022)
BACKGROUND: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina. OBJECTIVE: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. METHODS: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant. RESULTS: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes. CONCLUSION: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD.

Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-β Burden. - Baradaran, Hediyeh; Peloso, Gina M; Polak, Joseph F; Killiany, Ronald J; Ghosh, Saptaparni; DeCarli, Charles S; Thibault, Emma G; Sperling, Reisa A; Johnson, Keith A; Beiser, Alexa; Romero, Jose R; Seshadri, Sudha (J Alzheimers Dis, 2022)
BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden. OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden. METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. RESULTS: Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ. CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer's Disease Spectrum. - Teipel, Stefan J; Dyrba, Martin; Ballarini, Tommaso; Brosseron, Frederic; Bruno, Davide; Buerger, Katharina; Cosma, Nicoleta-Carmen; Dechent, Peter; Dobisch, Laura; Düzel, Emrah; Ewers, Michael; Fliessbach, Klaus; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. OBJECTIVE: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. METHODS: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. RESULTS: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. CONCLUSION: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.
Keywords: Aged; Alzheimer Disease; Basal Forebrain; Biomarkers; Cholinergic Agents; Cognitive Dysfunction; Cohort Studies; Female; Humans; Inflammation; Magnetic Resonance Imaging; Male

Association of COVID-19 with New-Onset Alzheimer's Disease. - Wang, Lindsey; Davis, Pamela B; Volkow, Nora D; Berger, Nathan A; Kaelber, David C; Xu, Rong (J Alzheimers Dis, 2022)
An infectious etiology of Alzheimer's disease has been postulated for decades. It remains unknown whether SARS-CoV-2 viral infection is associated with increased risk for Alzheimer's disease. In this retrospective cohort study of 6,245,282 older adults (age ≥65 years) who had medical encounters between 2/2020-5/2021, we show that people with COVID-19 were at significantly increased risk for new diagnosis of Alzheimer's disease within 360 days after the initial COVID-19 diagnosis (hazard ratio or HR:1.69, 95% CI: 1.53-1.72), especially in people age ≥85 years and in women. Our findings call for research to understand the underlying mechanisms and for continuous surveillance of long-term impacts of COVID-19 on Alzheimer's disease.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; COVID-19; COVID-19 Testing; Female; Humans; Retrospective Studies; SARS-CoV-2

Associations Between Brainstem Volume and Alzheimer's Disease Pathology in Middle-Aged Individuals of the Framingham Heart Study. - Jacobs, Heidi I L; O'Donnell, Adrienne; Satizabal, Claudia L; Lois, Cristina; Kojis, Daniel; Hanseeuw, Bernard J; Thibault, Emma; Sanchez, Justin S; Buckley, Rachel F; Yang, Qiong; DeCarli, Charles; Killiany, Ron; et al. (J Alzheimers Dis, 2022)
The brainstem is among the first regions to accumulate Alzheimer's disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-β or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

Associations Between Intrathecal Levels of Vitamin D, Cytokines, and Core Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. - Soares, Jelena Zugic; Valeur, Jørgen; Šaltytė Benth, Jūratė; Knapskog, Anne-Brita; Selbæk, Geir; Bogdanovic, Nenad; Pettersen, Renate (J Alzheimers Dis, 2022)
BACKGROUND: Several studies have examined association between vitamin D levels in serum and cognition, but little is known of vitamin D levels in cerebrospinal fluid (CSF) and association with Alzheimer's disease (AD). OBJECTIVE: In this cross-sectional, explorative study we investigated possible associations of vitamin D in CSF with biomarkers for AD, amyloid-β, tau protein/phosphorylated tau protein in CSF, and with the cytokines IL-6, IL-8, and TNF-α in CSF in patients with cognitive impairment and cognitively healthy controls. METHODS: We included 100 outpatients ≥65 years referred for assessment of cognitive impairment and 76 age- and sex-matched cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D), amyloid-β, tau protein and phosphorylated tau protein, as well as IL-6, IL-8, and TNF-α, were analyzed in CSF in both groups. RESULTS: Higher levels of 25(OH)D in CSF in all groups together were associated with lower levels of tau protein (p = 0.01) and phosphorylated tau protein (p = 0.005). We found no association between 25(OH)D levels in CSF and pathological levels of amyloid-β in CSF nor levels of IL-6 or TNF-α in CSF. Higher levels of 25(OH)D in CSF were associated with higher levels of IL-8 in CSF (p = 0.002). However, vitamin D explained only 6% of variance in IL-8. There was no significant difference between the patient groups and the control group regarding the association between 25(OH)D in CSF and any of the three cytokines in CSF. CONCLUSION: Participants with higher CSF levels of 25(OH)D exhibited reduced CSF levels of tau protein and phosphorylated tau protein.

Associations Between Vascular Risk Factor and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia. - Rundek, Tatjana; Del Brutto, Victor; Goryawala, Mohammed; Dong, Chuanhui; Agudelo, Christian; Saporta, Anita Seixas; Merritt, Stacy; Camargo, Christian; Ariko, Taylor; Loewenstein, David A; Duara, Ranjan; Haq, Ihtsham (J Alzheimers Dis, 2022)
BACKGROUND: Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste. OBJECTIVE: We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk. METHODS: Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (<10), 2 (11-20), 3 (21-40), and 4 (>40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score. RESULTS: Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (β= 0.03/year, p <  0.0001), Hispanic ethnicity (β= 0.29, p = 0.01), education (β= 0.04/year, p = 0.04), and coronary bypass surgery (β= 0.93, p = 0.02). CSO PVS only associated with age (β= 0.03/year, p <  0.01). APOE4 and amyloid-β were not associated with PVS. CONCLUSION: BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. - Frenzel, Stefan; Bis, Josh C; Gudmundsson, Elias F; O'Donnell, Adrienne; Simino, Jeannette; Yaqub, Amber; Bartz, Traci M; Brusselle, Guy G O; Bülow, Robin; DeCarli, Charles S; Ewert, Ralf; Gharib, Sina A; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables. METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

Augmenting Imaging Biomarker Performance with Blood-Based Gene Expression Levels for Predicting Alzheimer's Disease Progression. - Dobromyslin, Vitaly I; Megherbi, Dalila B (J Alzheimers Dis, 2022)
BACKGROUND: Structural brain imaging metrics and gene expression biomarkers have previously been used for Alzheimer's disease (AD) diagnosis and prognosis, but none of these studies explored integration of imaging and gene expression biomarkers for predicting mild cognitive impairment (MCI)-to-AD conversion 1-2 years into the future. OBJECTIVE: We investigated advantages of combining gene expression and structural brain imaging features for predicting MCI-to-AD conversion. Selection of the differentially expressed genes (DEGs) for classifying cognitively normal (CN) controls and AD patients was benchmarked against previously reported results. METHODS: The current work proposes integrating brain imaging and blood gene expression data from two public datasets (ADNI and ANM) to predict MCI-to-AD conversion. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated in the two independents patient cohorts. RESULTS: Combining DEGs and imaging biomarkers for predicting MCI-to-AD conversion yielded 0.832-0.876 receiver operating characteristic (ROC) area under the curve (AUC), which exceeded the 0.808-0.840 AUC from using the imaging features alone. With using only three DEGs, the CN versus AD predictive model achieved 0.718, 0.858, and 0.873 cross-validation AUC for the ADNI, ANM1, and ANM2 datasets. CONCLUSION: For the first time we show that combining gene expression and imaging biomarkers yields better predictive performance than using imaging metrics alone. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated to produce consistent results in the two independents patient cohorts. Using an improved feature selection, we show that predictive models with fewer gene expression probes can achieve competitive performance.

Automated Early Detection of Alzheimer's Disease by Capturing Impairments in Multiple Cognitive Domains with Multiple Drawing Tasks. - Kobayashi, Masatomo; Yamada, Yasunori; Shinkawa, Kaoru; Nemoto, Miyuki; Nemoto, Kiyotaka; Arai, Tetsuaki (J Alzheimers Dis, 2022)
BACKGROUND: Automatic analysis of the drawing process using a digital tablet and pen has been applied to successfully detect Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, most studies focused on analyzing individual drawing tasks separately, and the question of how a combination of drawing tasks could improve the detection performance thus remains unexplored. OBJECTIVE: We aimed to investigate whether analysis of the drawing process in multiple drawing tasks could capture different, complementary aspects of cognitive impairments, with a view toward combining multiple tasks to effectively improve the detection capability. METHODS: We collected drawing data from 144 community-dwelling older adults (27 AD, 65 MCI, and 52 cognitively normal, or CN) who performed five drawing tasks. We then extracted motion- and pause-related drawing features for each task and investigated the statistical associations of the features with the participants' diagnostic statuses and cognitive measures. RESULTS: The drawing features showed gradual changes from CN to MCI and then to AD, and the changes in the features for each task were statistically associated with cognitive impairments in different domains. For classification into the three diagnostic categories, a machine learning model using the features from all five tasks achieved a classification accuracy of 75.2%, an improvement by 7.8% over that of the best single-task model. CONCLUSION: Our results demonstrate that a common set of drawing features from multiple drawing tasks can capture different, complementary aspects of cognitive impairments, which may lead to a scalable way to improve the automated detection of AD and MCI.

Avoiding Over-Reliance on Multi-Domain Interventions for Dementia Prevention. - Daly, Timothy; Mastroleo, Ignacio; Migliaccio, Raffaella (J Alzheimers Dis, 2022)
Given the unknown therapeutic value of targeting Alzheimer's disease pathology and the discovery of robust risk factors for dementia, non-pharmacological risk reduction (RR) is increasingly offered as an alternative to targeting Alzheimer's disease pathology. While RR will surely be a useful tool to make public health gains, we propose solutions to three possible issues with over-reliance on multi-domain interventions to achieve RR: limited individual impact, an exclusive focus on later life, and overlooking social determinants of dementia. We argue in favor of a broader debate within the research community and greater society about how different therapeutic avenues should be explored.
Keywords: Alzheimer Disease; Humans; Risk Factors; Risk Reduction Behavior

B Vitamin Supplementation Slows Cognitive Decline in Mild Cognitive Impairment Patients with Frontal Lobe Atrophy. - Gong, Xianmin; Shi, Lin; Wu, Yuanyuan; Luo, Yishan; Kwok, Timothy (J Alzheimers Dis, 2022)
BACKGROUND: The effects of B vitamins on mild cognitive impairment (MCI) patients' cognition have been mixed, suggesting the existence of moderating factors. OBJECTIVE: A post hoc analysis of a negative B vitamin trial was performed to examine the potential modulating effect of regional brain atrophy on the cognitive response to B vitamins in MCI patients. METHODS: In the 24-month randomized trial, 279 MCI outpatients took 500μ#x03BC;g methylcobalamin and 400μ#x03BC;g folic acid once per day or placebo tablets once per day. Sixty-four aspirin users were excluded from analysis as aspirin use has been found to have significant negative interaction effects. Subjects were followed up at months 12 and 24. The primary cognitive outcome was clinical dementia rating scale sum of boxes (CDR_SOB). In a subgroup of 83 subjects, MRI brain scans were performed at baseline to estimate regional brain atrophy ratios. RESULTS: Among the trial subjects who had MRI data, B vitamin supplementation had no significant effect on CDR_SOB, despite having significant homocysteine lowering effects. The atrophy ratio of the left frontal lobe significantly moderated the effect of B vitamin supplementation on CDR_SOB, after adjusting for confounders, in that B vitamin supplementation was associated with lower CDR_SOB scores (i.e., better cognitive function) at the 24th month among those patients with above median atrophy ratios, but not among those with lower atrophy ratios, in the left frontal lobe. CONCLUSION: B vitamins may be more effective in slowing down cognitive decline in MCI patients with atrophy in the left frontal lobe.

Barriers to Effective Memory Assessments for Alzheimer's Disease. - Parra, Mario A (J Alzheimers Dis, 2022)
Recently, Alzheimer's Disease International (ADI) stressed that around 75% of people living with dementia globally are still not receiving a diagnosis. In this commentary, I reflect on how efforts towards better cognitive assessments, particularly of memory, can be aligned and harmonized to contribute to such needs. I highlight some barriers that ongoing collaborations and trials are facing and their potential drivers. I suggest some strategies that can help overcome them and in so doing, integrate research agendas. We need to ignite the debate towards strategies that can help level the playfield to tackle Alzheimer's disease with true global solutions.
Keywords: Alzheimer Disease; Cognition; Cognition Disorders; Humans; Longitudinal Studies

Behavioral and Psychological Symptoms of Dementia in Different Dementia Disorders: A Large-Scale Study of 10,000 Individuals. - Schwertner, Emilia; Pereira, Joana B; Xu, Hong; Secnik, Juraj; Winblad, Bengt; Eriksdotter, Maria; Nägga, Katarina; Religa, Dorota (J Alzheimers Dis, 2022)
BACKGROUND: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden. OBJECTIVE: To characterize BPSD in Alzheimer's disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities. METHODS: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs. RESULTS: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD. CONCLUSION: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.
Keywords: Alzheimer Disease; Behavioral Symptoms; Dementia, Vascular; Frontotemporal Dementia; Hallucinations; Humans; Parkinson Disease

Better Subjective Sleep Quality Partly Explains the Association Between Self-Reported Physical Activity and Better Cognitive Function. - Cheval, Boris; Maltagliati, Silvio; Sieber, Stefan; Cullati, Stéphane; Zou, Liye; Ihle, Andreas; Kramer, Arthur F; Yu, Qian; Sander, David; Boisgontier, Matthieu P (J Alzheimers Dis, 2022)
BACKGROUND: Physical activity has been associated with better cognitive function and better sleep quality. Yet, whether the beneficial effect of physical activity on cognitive function can be explained by an indirect pathway involving better sleep quality is unclear. OBJECTIVE: To investigate whether sleep quality mediates the association between physical activity and cognitive function in adults 50 years of age or older. METHODS: 86,541 community-dwelling European adults were included in the study. Physical activity and sleep quality were self-reported. Indicators of cognitive function (immediate recall, delayed recall, verbal fluency) were assessed using objective tests. All measures were collected six times between 2004 and 2017. The mediation was tested using multilevel mediation analyses. RESULTS: Results showed that self-reported physical activity was associated with better self-reported sleep quality, which was associated with better performance in all three indicators of cognitive function, demonstrating an indirect effect of physical activity on cognitive function through sleep quality. The mediating effect of sleep quality accounted for 0.41%, 1.46%, and 8.88% of the total association of physical activity with verbal fluency, immediate recall, and delayed recall, respectively. CONCLUSION: These findings suggest that self-reported sleep quality partly mediates the association between self-reported physical activity and cognitive function. These results need to be confirmed by device-based data of physical activity and sleep quality.
Keywords: Cognition; Exercise; Humans; Self Report; Sleep; Sleep Quality

Bifidobacterium breve MCC1274 Supplementation Increased the Plasma Levels of Metabolites with Potential Anti-Oxidative Activity in APP Knock-In Mice. - Ohno, Kazuya; Abdelhamid, Mona; Zhou, Chunyu; Jung, Cha-Gyun; Michikawa, Makoto (J Alzheimers Dis, 2022)
BACKGROUND: We previously reported the effects of a probiotic strain, Bifidobacterium breve MCC1274, in improving cognitive function in preclinical and clinical studies. Recently, we demonstrated that supplementation of this strain led to decreased amyloid-β production, attenuated microglial activation, and suppressed inflammation reaction in the brain of APP knock-in (AppNL - G - F) mice. OBJECTIVE: In this study, we investigated the plasma metabolites to reveal the mechanism of action of this probiotic strain in this Alzheimer's disease (AD)-like model. METHODS: Three-month-old mice were orally supplemented with B. breve MCC1274 or saline for four months and their plasma metabolites were comprehensively analyzed using CE-FTMS and LC-TOFMS. RESULTS: Principal component analysis showed a significant difference in the plasma metabolites between the probiotic and control groups (PERMANOVA, p = 0.03). The levels of soy isoflavones (e.g., genistein) and indole derivatives of tryptophan (e.g., 5-methoxyindoleacetic acid), metabolites with potent anti-oxidative activities were significantly increased in the probiotic group. Moreover, there were increased levels of glutathione-related metabolites (e.g., glutathione (GSSG)_divalent, ophthalmic acid) and TCA cycle-related metabolites (e.g., 2-Oxoglutaric acid, succinic acid levels) in the probiotic group. Similar alternations were observed in the wild-type mice by the probiotic supplementation. CONCLUSION: These results suggest that the supplementation of B. breve MCC1274 enhanced the bioavailability of potential anti-oxidative metabolites from the gut and addressed critical gaps in our understanding of the gut-brain axis underlying the mechanisms of the probiotic action of this strain in the improvement of cognitive function.

A Bioinformatics Approach Toward Unravelling the Synaptic Molecular Crosstalk Between Alzheimer's Disease and Diabetes. - Alves, Steven R; da Cruz E Silva, Cristóvão; Martins, Ilka; Henriques, Ana Gabriela; da Cruz E Silva, Odete A B (J Alzheimers Dis, 2022)
BACKGROUND: Increasing evidence links impaired brain insulin signaling and insulin resistance to the development of Alzheimer's disease (AD). OBJECTIVE: This evidence prompted a search for molecular players common to AD and diabetes mellitus (DM). METHODS: The work incorporated studies based on a primary care-based cohort (pcb-Cohort) and a bioinformatics analysis to identify central nodes, that are key players in AD and insulin signaling (IS) pathways. The interactome for each of these key proteins was retrieved and network maps were developed for AD and IS. Synaptic enrichment was performed to reveal synaptic common hubs. RESULTS: Cohort analysis showed that individuals with DM exhibited a correlation with poor performance in the Mini-Mental State Examination (MMSE) cognitive test. Additionally, APOE ɛ2 allele carriers appear to potentially be relatively more protected against both DM and cognitive deficits. Ten clusters were identified in this network and 32 key synaptic proteins were common to AD and IS. Given the relevance of signaling pathways, another network was constructed focusing on protein kinases and protein phosphatases, and the top 6 kinase nodes (LRRK2, GSK3B, AKT1, EGFR, MAPK1, and FYN) were further analyzed. CONCLUSION: This allowed the elaboration of signaling cascades directly impacting AβPP and tau, whereby distinct signaling pathway play a major role and strengthen an AD-IS link at a molecular level.

Blood Pressure and Later-Life Cognition in Hispanic and White Adults (BP-COG): A Pooled Cohort Analysis of ARIC, CARDIA, CHS, FOS, MESA, and NOMAS. - Levine, Deborah A; Gross, Alden L; Briceño, Emily M; Tilton, Nicholas; Whitney, Rachael; Han, Dehua; Giordani, Bruno J; Sussman, Jeremy B; Hayward, Rodney A; Burke, James F; Elkind, Mitchell S V; Moran, Andrew E; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. OBJECTIVE: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. METHODS: Pooled cohort study of individual participant data from six cohorts (1971-2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1-Q3, 5.2-20.1) years. RESULTS: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. CONCLUSION: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

A Blood Test for Alzheimer's Disease: It's about Time or Not Ready for Prime Time? - Galasko, Douglas R; Grill, Joshua D; Lingler, Jennifer H; Heidebrink, Judith L (J Alzheimers Dis, 2022)
A blood test for Alzheimer's disease is now available for clinical use in persons with cognitive impairment. This is an extraordinary milestone, though the amyloid-based PrecivityAD™ test is not without limitations. Pre and post-test counseling are essential. Phosphorylated tau blood tests are likely to follow soon. When used in conjunction with an appropriate clinical evaluation, blood tests provide the opportunity for an early, accurate, and accessible diagnosis of Alzheimer's disease. Standalone use, however, carries a significant risk of misinterpretation and is strongly discouraged. Now is the time to develop appropriate use criteria to guide the use of these promising assays.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Hematologic Tests; Humans; tau Proteins

Blood Tests for Alzheimer's Disease: Increasing Efforts to Expand and Diversify Research Participation Is Critical for Widespread Validation and Acceptance. - Karikari, Thomas K (J Alzheimers Dis, 2022)
The recent academic and commercial development, and regulatory approvals, of blood-based Alzheimer's disease (AD) biomarkers are breakthrough developments of immense potential. However, clinical validation studies and therapeutic trial applications are limited almost exclusively to non-Hispanic White cohorts often including highly-educated, high-earning participants. This commentary argues that the true benefits of blood tests for AD will be realized by active inclusion of diverse groups including minoritized populations, people of socioeconomic status different from those included in existing cohorts, and residents of low- and middle-income countries. The article discusses key factors that are critical for a successful implementation of diversity programs.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Hematologic Tests; Humans; tau Proteins

Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease Display Altered Key Protein Levels Including Cell Type-Specific Markers. - Huang, Yiyao; Driedonks, Tom A P; Cheng, Lesley; Rajapaksha, Harinda; Routenberg, David A; Nagaraj, Rajini; Redding, Javier; Arab, Tanina; Powell, Bonita H; Pletniková, Olga; Troncoso, Juan C; Zheng, Lei; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer's disease (AD). Extracellular vesicles (EVs) may also leave the brain to betray the state of the CNS in the periphery. Only a few studies have profiled the proteome of bdEVs and source brain tissue. Additionally, studies focusing on bdEV cell type-specific surface markers are rare. OBJECTIVE: We aimed to reveal the pathological mechanisms inside the brain by profiling the tissue and bdEV proteomes in AD patients. In addition, to indicate targets for capturing and molecular profiling of bdEVs in the periphery, CNS cell-specific markers were profiled on the intact bdEV surface. METHODS: bdEVs were separated and followed by EV counting and sizing. Brain tissue and bdEVs from age-matched AD patients and controls were then proteomically profiled. Total tau (t-tau), phosphorylated tau (p-tau), and antioxidant peroxiredoxins (PRDX) 1 and 6 were measured by immunoassay in an independent bdEV separation. Neuron, microglia, astrocyte, and endothelia markers were detected on intact EVs by multiplexed ELISA. RESULTS: Overall, concentration of recovered bdEVs was not affected by AD. Proteome differences between AD and control were more pronounced for bdEVs than for brain tissue. Levels of t-tau, p-tau, PRDX1, and PRDX6 were significantly elevated in AD bdEVs compared with controls. Release of certain cell-specific bdEV markers was increased in AD. CONCLUSION: Several bdEV proteins are involved in AD mechanisms and may be used for disease monitoring. The identified CNS cell markers may be useful tools for peripheral bdEV capture.

Burden of Insomnia and Sleep Disturbances and the Impact of Sleep Treatments in Patients with Probable or Possible Alzheimer's Disease: A Structured Literature Review. - Benca, Ruth; Herring, W Joseph; Khandker, Rezaul; Qureshi, Zaina P (J Alzheimers Dis, 2022)
BACKGROUND: Sleep disturbances are frequent in Alzheimer's disease (AD). OBJECTIVE: To summarize the impact of sleep disturbances on AD patients and their caregivers and the effects of currently available sleep therapies. METHODS: Published studies (January 1985-March 2020) assessing the burden associated with insomnia/sleep disturbances in the AD population and insomnia treatment effects were identified by searching PubMed, Embase, and Cochrane Library and screened against inclusion criteria. RESULTS: 58 studies assessing patient and caregiver burden, institutionalization, and insomnia treatments in AD patients with sleep disturbances were identified. Sleep disturbances were associated with worse cognition, functional ability, and behavioral and neuropsychological functioning. Health status and quality of life of both patients and caregivers were reduced in the presence of sleep disturbances. Sleep disturbances were also associated with institutionalization. Although significant associations between sleep problems and clinical outcomes were apparent, there was generally no control for other influencing factors (e.g., cognitive status). Bright light and behavioral therapies as well as drugs showed some promise in AD patients, but studies were primarily small and limited data were available, particularly in regard to the effect on associated clinical burden. CONCLUSION: Sleep disturbances are a significant problem for AD patients and caregivers, associated with behavioral and psychological problems and cognitive decline. However, they remain poorly characterized and under-researched. As the global population is aging and AD is on thes rise, data from larger, prospective trials are required to fully understand the clinical correlates of sleep disturbances and the impact insomnia treatments can have.
Keywords: Alzheimer Disease; Caregivers; Humans; Prospective Studies; Quality of Life; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders

Can Diet Supplements of Macular Pigment of Lutein, Zeaxanthin, and Meso-zeaxanthin Affect Cognition? - Wang, Hongwei; Wang, Ge; Billings, Rebecca; Li, Daniel; Haase, Shakaye R; Wheeler, Pariya F; Vance, David E; Li, Wei (J Alzheimers Dis, 2022)
BACKGROUND: Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) are collectively called macular pigment. MZ can be converted from L in the macula. In the recent decade, many studies have been performed to investigate the effects for taking carotenoids, especially L and Z or L, Z, and MZ, as diet supplements on human health. OBJECTIVE: We examined if diet supplements of L + Z or L + Z + MZ have effects on cognitive function in adults. METHODS: A systemic literature search was performed in March 2021 with the following keywords: lutein, zeaxanthin, meso-zeaxanthin, cognition, cognitive, and macular pigment. The searched databases included Medline EBSCOhost, Scopus, Elsevier, Cochrane Library, ProQuest, and ClinicalTrials.gov. Findings from eight clinical trials were presented as the strongest evidence on the studied topic. RESULTS: Most studies have found that macular pigments (L + Z) in blood or macula are positively correlated with cognitive performance. As an index of the amount of macular pigments in the brain, macular pigment optical density is related to cognitive performance in adults. In addition, there is an inverse relationship between a higher amount of macular pigment in the blood and lower risk of mild cognitive impairments or Alzheimer's disease. Based on the findings from the clinical trials, diet supplements of L + Z or L + Z + MZ are associated with improved cognition in adults. CONCLUSION: The diet supplements of L + Z or L + Z+MZ are associated with better cognitive functioning, which may be via their beneficial effects on the vision.

Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old. - Lachner, Christian; Day, Gregory S; Camsari, Gamze Balci; Kouri, Naomi; Ertekin-Taner, Nilufer; Boeve, Bradley F; Labuzan, Sydney A; Lucas, John A; Thompson, E Aubrey; Siddiqui, Habeeba; Crook, Julia E; Cabrera-Rodriguez, Janisse N; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. OBJECTIVE: Investigate vascular and cancer contributions to dementia and neuropathology in oldest-old. METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p <  0.01) and lower Braak stage (p = 0.01). CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

"Captive by the Uncertainty"-Experiences with Anticipatory Guidance for People Living with Dementia and Their Caregivers at a Specialty Dementia Clinic. - Shafir, Adi; Ritchie, Christine S; Garrett, Sarah B; Bernstein Sideman, Alissa; Naasan, Georges; Merrilees, Jennifer; Widera, Eric; Flint, Lynn; Harrison, Krista L (J Alzheimers Dis, 2022)
BACKGROUND: After a diagnosis of Alzheimer's disease and related disorders, people living with dementia (PWD) and caregivers wonder what disease trajectory to expect and how to plan for functional and cognitive decline. This qualitative study aimed to identify patient and caregiver experiences receiving anticipatory guidance about dementia from a specialty dementia clinic. OBJECTIVE: To examine PWD and caregiver perspectives on receiving anticipatory guidance from a specialty dementia clinic. METHODS: We conducted semi-structured interviews with PWD, and active and bereaved family caregivers, recruited from a specialty dementia clinic. Interviews were recorded, transcribed, and systematically summarized. Thematic analysis identified anticipatory guidance received from clinical or non-clinical sources and areas where respondents wanted additional guidance. RESULTS: Of 40 participants, 9 were PWD, 16 were active caregivers, and 15 were bereaved caregivers. PWD had a mean age of 75 and were primarily male (n = 6/9); caregivers had a mean age of 67 and were primarily female (n = 21/31). Participants felt they received incomplete or "hesitant" guidance on prognosis and expected disease course via their clinicians and filled the gap with information they found via the internet, books, and support groups. They appreciated guidance on behavioral, safety, and communication issues from clinicians, but found more timely and advance guidance from other non-clinical sources. Guidance on legal and financial planning was primarily identified through non-clinical sources. CONCLUSION: PWD and caregivers want more information about expected disease course, prognosis, and help planning after diagnosis. Clinicians have an opportunity to improve anticipatory guidance communication and subsequent care provision.
Keywords: Aged; Alzheimer Disease; Caregivers; Dementia; Female; Humans; Male; Qualitative Research; Uncertainty

Caregiver Tele-Assistance for Reduction of Emotional Distress During the COVID-19 Pandemic. Psychological Support to Caregivers of People with Dementia: The Italian Experience. - Rotondo, Emanuela; Galimberti, Daniela; Mercurio, Matteo; Giardinieri, Giulia; Forti, Sara; Vimercati, Roberto; Borracci, Vittoria; Fumagalli, Giorgio G; Pietroboni, Anna M; Carandini, Tiziana; Nobili, Alessandro; Scarpini, Elio; et al. (J Alzheimers Dis, 2022)
BACKGROUND: COVID-19 pandemic worsened vulnerability of patients with dementia (PWD). This new reality associated with government restriction and isolation worsened stress burden and psychological frailties in PWD caregivers. OBJECTIVE: To give tele-psychological support to caregivers and evaluate the effect of this intervention by quantifying stress burden and quality of life during the first COVID-19 lockdown. METHODS: 50 caregivers were divided into two groups: "Caregiver-focused group" (Cg) and "Patient-focused group" (Pg). Both groups received telephone contact every 2 weeks over a 28-week period, but the content of the call was different: in Cg, caregivers answered questions about the state of the PWD but also explored their own emotional state, stress burden, and quality of life. In Pg instead, telephone contacts were focused only on the PWD, and no evaluation regarding the caregiver mood or state of stress was made. Psychometric scales were administered to evaluate COVID-19 impact, stress burden, and quality of life. RESULTS: Considering the time of intervention, from baseline (W0) to W28, Zarit Burden Interview and Quality of Life-caregiver questionnaires remained unchanged in Cg as compared with baseline (p > 0.05), whereas they worsened significantly in Pg (p < 0.01), showing increased stress over time and decreased quality of life in this group. Moreover, Impact on Event Scale values improved over the weeks in Cg (p = 0.015), while they remained unchanged in Pg (p = 0.483). CONCLUSION: Caregivers who received telephone support about their mood and stress burden did not worsen their psychological state during the time of intervention, as did instead those who did not get such support.
Keywords: Aged; Aged, 80 and over; Caregiver Burden; Caregivers; COVID-19; Dementia; Female; Humans; Italy; Male; Middle Aged; Psychological Distress; Psychosocial Support Systems; Quality of Life; Surveys and Questionnaires; Telephone

Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort. - Chaudhary, Shefali; Zhornitsky, Simon; Chao, Herta H; van Dyck, Christopher H; Li, Chiang-Shan R (J Alzheimers Dis, 2022)
BACKGROUND: Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. OBJECTIVE: To identify neuroanatomical correlates of AD-associated apathy. METHODS: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale. RESULTS: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. CONCLUSION: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.
Keywords: Aged; Alzheimer Disease; Apathy; Atrophy; Basal Ganglia; Brain; Cognitive Dysfunction; Cohort Studies; Gray Matter; Gyrus Cinguli; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Prefrontal Cortex

Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation. - Morrow, Autumn; Panyard, Daniel J; Deming, Yuetiva K; Jonaitis, Erin; Dong, Ruocheng; Vasiljevic, Eva; Betthauser, Tobey J; Kollmorgen, Gwendlyn; Suridjan, Ivonne; Bayfield, Anna; Van Hulle, Carol A; Zetterberg, Henrik; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. OBJECTIVE: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. METHODS: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. RESULTS: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. CONCLUSION: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.

Characterization of Mild Cognitive Impairment and Dementia among Community-Dwelling Mexican Americans and Non-Hispanic Whites. - O'Bryant, Sid E; Petersen, Melissa; Hall, James; Johnson, Leigh A; Barber, Robert; Phillips, Nicole; Braskie, Meredith N; Yaffe, Kristine; Rissman, Robert; Toga, Arthur (J Alzheimers Dis, 2022)
BACKGROUND: Despite tremendous advancements in the field, our understanding of mild cognitive impairment (MCI) and Alzheimer's disease (AD) among Mexican Americans remains limited. OBJECTIVE: The aim of this study was to characterize MCI and dementia among Mexican Americans and non-Hispanic whites. METHODS: Baseline data were analyzed from n = 1,705 (n = 890 Mexican American; n = 815 non-Hispanic white) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD). RESULTS: Among Mexican Americans, age (OR = 1.07), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.01) were associated with dementia, but none of these factors were associated with MCI. Among non-Hispanic whites, male gender (OR = 0.33), neighborhood deprivation (OR = 1.34), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.03) were associated with MCI, while depression (OR = 1.09) and APOEɛ4 genotype (OR = 4.38) were associated with dementia. CONCLUSION: Findings from this study revealed that the demographic, clinical, sociocultural and biomarker characteristics of MCI and dementia are different among Mexican Americans as compared to non-Hispanic whites.

Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia? - Tran, Shirley; Kuruppu, Sanjaya; Rajapakse, Niwanthi W (J Alzheimers Dis, 2022)
Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.
Keywords: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Brain; Cytokines; Dementia, Vascular; Humans; Hypertension; Inflammation; Peptide Fragments; Renin-Angiotensin System

Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function. - Nidadavolu, Lolita S; Feger, Danielle; Wu, Yuqiong; Grodstein, Francine; Gross, Alden L; Bennett, David A; Walston, Jeremy D; Oh, Esther S; Abadir, Peter M (J Alzheimers Dis, 2022)
BACKGROUND: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA). OBJECTIVE: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults. METHODS: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education. RESULTS: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up. CONCLUSION: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.

Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints. - Andriuta, Daniela; Si-Ahmed, Cherifa; Roussel, Martine; Constans, Jean-Marc; Makki, Malek; Aarabi, Ardalan; Basille, Damien; Andrejak, Claire; Godefroy, Olivier (J Alzheimers Dis, 2022)
BACKGROUND: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants. OBJECTIVE: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants. METHODS: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance. RESULTS: Repeated ANOVA showed a group effect (p = 0.0001) due to overall lower performance for patients and a domain effect (p = 0.0001) due to a lower (p = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2 = 0.319, p = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus. CONCLUSION: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.
Keywords: Cognition; COVID-19; Humans; Leukoaraiosis; Magnetic Resonance Imaging; Neurocognitive Disorders; Neuropsychological Tests; Oxygen; White Matter

Clinical Utility of Cerebrospinal Fluid Aβ42 and Tau Measures in Diagnosing Mild Cognitive Impairment in Early Onset Dementia. - Hosseini, Akram A; Brown, Thomas; Mannino, Luca; Gran, Bruno; Junaid, Kehinde; Mukaetova-Ladinska, Elizabeta B (J Alzheimers Dis, 2022)
BACKGROUND: The differentiation of a preclinical or prodromal Alzheimer's disease (AD) is challenging particularly in patients with early onset Alzheimer's or related dementias (EOARD). We report our experience on diagnostic lumbar puncture to diagnose EOARD at a tertiary neurocognitive referral center in Nottingham, England from March 2018 to October 2020. OBJECTIVE: To assess amyloid-β42 (Aβ42), total tau, and Thr181-phosphorylated tau (p-tau) measurements in the cerebrospinal fluid (CSF) in patients with mild cognitive impairment (MCI) and in relation to their follow-up cognitive performance. METHODS: Thirty participants aged 32-68 years old (mean 59 years; 57% female) were included. Clinical diagnosis was based on clinical presentation, neurocognitive profile, neuroradiological features (MRI, FDG-PET CT) and CSF Aβ42, total tau, and p-tau measurements. RESULTS: Patients with MCI who progressed to AD (prodromal AD) had significantly higher CSF total (797.63 pg/ml) and p-tau (82.31 pg/ml), and lower Aβ42 levels (398.94 pg/ml) in comparison to their counterparts with stable MCI (total tau 303.67 pg/ml, p-tau 43.56 pg/ml, Aβ42 873.44 pg/ml) (p <  0.01 for CSF total and p-tau measures and p <  0.0001 for CSF Aβ42 measures). None of the CSF biomarkers correlated with any of the cognitive performance measures. Principal component analysis confirmed that the clinical diagnosis of MCI secondary to AD, namely prodromal AD (as per NIA-AA criteria) in younger adults, was associated with decreased CSF Aβ42. CONCLUSION: In early onset AD, low levels of CSF Aβ42 appear to be more sensitive than total and p-tau measures in differentiating AD MCI from other forms of dementia. Further work on larger samples of EOARD in clinical practice will address the cost effectiveness of making an earlier diagnosis.

Cognitive Decline Risk Stratification in People with Late-Onset Epilepsy of Unknown Etiology: An Electroencephalographic Connectivity and Graph Theory Pilot Study. - Costa, Cinzia; Vecchio, Fabrizio; Romoli, Michele; Miraglia, Francesca; Nardi Cesarini, Elena; Alù, Francesca; Calabresi, Paolo; Rossini, Paolo Maria (J Alzheimers Dis, 2022)
BACKGROUND: Although people with late onset epilepsy of unknown etiology (LOEU) are at higher risk of cognitive decline compared to the general population, we still lack affordable tools to predict and stratify their risk of dementia. OBJECTIVE: This pilot-study investigates the potential application of electroencephalography (EEG) network small-world (SW) properties in predicting cognitive decline among patients with LOEU. METHODS: People diagnosed with LOEU and normal cognitive examination at the time of epilepsy diagnosis were included. Cerebrospinal fluid biomarkers, brain imaging, and neuropsychological assessment were performed at the time of epilepsy diagnosis. Baseline EEG was analyzed for SW properties. Patients were followed-up over time with neuropsychological testing to define the trajectory of cognitive decline. RESULTS: Over 5.1 years of follow-up, among 24 patients diagnosed with LOEU, 62.5% were female, mean age was 65.3 years, thirteen developed mild cognitive impairment (MCI), and four developed dementia. Patients with LOEU developing MCI had lower values of SW coefficients in the delta (p = 0.03) band and higher SW values in the alpha frequency bands (p = 0.02) compared to patients having normal cognition at last follow-up. The two separate ANOVAs, for low and alpha bands, confirmed an interaction between SW and cognitive decline at follow-up. A similar gradient was confirmed for patients developing dementia compared to those with normal cognitive function as well as to those developing MCI. CONCLUSION: Baseline EEG analysis through SW is worth investigating as an affordable, widely available tool to stratify LOEU patients for their risk of cognitive decline.
Keywords: Aged; Cognitive Dysfunction; Dementia; Electroencephalography; Epilepsy; Female; Humans; Male; Neuropsychological Tests; Pilot Projects; Risk Assessment

Cognitive Function Associated with Gut Microbial Abundance in Sucrose and S-Adenosyl-L-Methionine (SAMe) Metabolic Pathways. - Jeong, Sohyun; Huang, Li-Kai; Tsai, Ming-Ju; Liao, Yi-Tyng; Lin, Yow-Sien; Hu, Chaur-Jong; Hsu, Yi-Hsiang (J Alzheimers Dis, 2022)
BACKGROUND: Differential abundance of gut microbiota has found to be associated with Alzheimer's disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied. OBJECTIVE: We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI. METHODS: Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches. RESULTS: We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes), Anaerotruncus colihominis (Firmicutes), and Gordonibacter pamelaeae (Actinobacteria). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways was more enriched in AD with MCI than AD with dementia and significantly associated with higher cognitive function scores. CONCLUSION: Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline.
Keywords: Alzheimer Disease; Cognition; Cognitive Dysfunction; Gastrointestinal Microbiome; Humans; Metabolic Networks and Pathways; RNA, Ribosomal, 16S; S-Adenosylmethionine; Sucrose

Cognitive, Functional, and Emotional Changes During the COVID-19 Pandemic in Greek Patients with Neurocognitive Disorders. - Tsiakiri, Anna; Vlotinou, Pinelopi; Terzoudi, Aikaterini; Heliopoulos, Ioannis; Vadikolias, Konstantinos (J Alzheimers Dis, 2022)
BACKGROUND: Prolonged periods of social deprivation, such as COVID-19-related lockdowns, are associated with deleterious effects on cognitive functions. OBJECTIVE: The aim of this study was to gauge the effect of prolonged social isolation on the cognitive function of older adults with neurocognitive disorders. METHODS: We recruited 125 older adults with minor or major neurocognitive disorders divided into two groups. The control group was tested at the first period of the study (October 2018-May 2019), whereas the experimental group was evaluated at the second chronological period of the study (October 2020-May 2021) during the second wave of COVID-19. Neuropsychological tests were performed at baseline and six months after baseline. RESULTS: In the control group, significant changes in the scores from the Montreal Cognitive Assessment (MoCA; p = 0.049) and the Functional Rating Scale for Symptoms of Dementia (FRSSD; p = 0.005) were found between baseline and follow-up assessments, whereas no changes were identified in Mini-Mental State Examination (MMSE; p = 0.229) and Geriatric Depression Scale (GDS; p = 0.619) scores. In the experimental group, the scores from all neuropsychological tests (MoCA, MMSE, GDS, and FRSSD; p < 0.001 for all) were significantly different at follow-up when compared with those at baseline measurements. Moreover, significant deterioration of specific functions assessed in MMSE and FRSSD was detected, especially in the experimental group. CONCLUSION: This study highlights cognitive functions directly affected by social deprivation of individuals with neurocognitive disorders. The findings can be used in the rehabilitation from confinement and its negative consequences.
Keywords: Aged; Cognition; Cognitive Dysfunction; Communicable Disease Control; COVID-19; Greece; Humans; Neurocognitive Disorders; Neuropsychological Tests; Pandemics

Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer's Disease. - Nabirotchkin, Serguei; Bouaziz, Jan; Glibert, Fabrice; Mandel, Jonas; Foucquier, Julie; Hajj, Rodolphe; Callizot, Noëlle; Cholet, Nathalie; Guedj, Mickaël; Cohen, Daniel (J Alzheimers Dis, 2022)
BACKGROUND: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. OBJECTIVE: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases. METHODS: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. RESULTS: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. CONCLUSION: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer's disease.

Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach. - Timsina, Jigyasha; Gomez-Fonseca, Duber; Wang, Lihua; Do, Anh; Western, Dan; Álvarez, Ignacio; Aguilar, Miquel; Pastor, Pau; Henson, Rachel L; Herries, Elizabeth; Xiong, Chengjie; Schindler, Suzanne E; et al. (J Alzheimers Dis, 2022)
BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. METHODS: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r >  0.9). sTREM2 had a fair correlation (r >  0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.

A Comparison of Behavioral and Psychological Symptoms of Dementia (BPSD) and BPSD Sub-Syndromes in Early-Onset and Late-Onset Alzheimer's Disease. - Altomari, Natalia; Bruno, Francesco; Laganà, Valentina; Smirne, Nicoletta; Colao, Rosanna; Curcio, Sabrina; Di Lorenzo, Raffaele; Frangipane, Francesca; Maletta, Raffaele; Puccio, Gianfranco; Bruni, Amalia Cecilia (J Alzheimers Dis, 2022)
BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer's disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results. OBJECTIVE: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1. METHODS: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period. RESULTS: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences. CONCLUSION: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view.
Keywords: Affective Symptoms; Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Apathy; Behavioral Symptoms; Dementia; Female; Humans; Italy; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychomotor Agitation; Psychotic Disorders; Severity of Illness Index

Comparison of Steady-State Pharmacokinetics of Donepezil Transdermal Delivery System with Oral Donepezil. - Tariot, Pierre N; Braeckman, Rene; Oh, Charles (J Alzheimers Dis, 2022)
BACKGROUND: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States. OBJECTIVE: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil. METHODS: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5. RESULTS: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively). CONCLUSION: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.
Keywords: Adolescent; Adult; Alzheimer Disease; Cross-Over Studies; Donepezil; Humans; Middle Aged; Young Adult

A Comparison of Well-Being of Carers of People with Dementia and Their Ability to Manage Before and During the COVID-19 Pandemic: Findings from the IDEAL Study. - Gamble, Laura D; Parker, Sophie; Quinn, Catherine; Bennett, Holly Q; Martyr, Anthony; Sabatini, Serena; Pentecost, Claire; Collins, Rachel; Dawson, Eleanor; Hunt, Anna; Allan, Louise; Burns, Alistair; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. OBJECTIVE: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. METHODS: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the 'pre-pandemic group' (n = 312), assessed at two time points prior to the pandemic, and the 'pandemic group', assessed prior to and several months into the pandemic (n = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, were investigated using mixed effect modelling. RESULTS: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. CONCLUSIONS: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic.
Keywords: Adaptation, Psychological; Caregivers; COVID-19; Dementia; Humans; Pandemics; Quality of Life

The Correlation of Tau Levels with Blood Monocyte Count in Patients with Alzheimer's Disease. - Sun, Hao-Lun; Zhou, Fa-Ying; Chen, Dong-Wan; Tan, Cheng-Rong; Zeng, Gui-Hua; Liu, Yu-Hui; Wang, Jun; Bu, Xian-Le; Wang, Yan-Jiang; Li, Hui-Yun; Jin, Wang-Sheng (J Alzheimers Dis, 2022)
BACKGROUND: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer's disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. OBJECTIVE: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. METHODS: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. RESULTS: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. CONCLUSION: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Brain; Cognitive Dysfunction; Cohort Studies; Female; Humans; Male; Monocytes; tau Proteins

COVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences. - Baazaoui, Narjes; Iqbal, Khalid (J Alzheimers Dis, 2022)
COVID-19 emerged as a global pandemic starting from Wuhan in China and spread at a lightning speed to the rest of the world. One of the potential long-term outcomes that we speculate is the development of neurodegenerative diseases as a long-term consequence of SARS-CoV-2 especially in people that have developed severe neurological symptoms. Severe inflammatory reactions and aging are two very strong common links between neurodegenerative diseases and COVID-19. Thus, patients that have very high viral load may be at high risk of developing long-term adverse neurological consequences such as dementia. We hypothesize that people with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and aged people are at higher risk of getting the COVID-19 than normal adults. The basis of this hypothesis is the fact that SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 to enter the host cell and that this interaction is calcium-dependent. This could then suggest a direct relationship between neurodegenerative diseases, ACE-2 expression, and the susceptibility to COVID-19. The analysis of the available literature showed that COVID-19 virus is neurotropic and was found in the brains of patients infected with this virus. Furthermore, that the risk of having the infection increases with dementia and that infected people with severe symptoms could develop dementia as a long-term consequence. Dementia could be developed following the acceleration of the spread of prion-like proteins. In the present review we discuss current reports concerning the prevalence of COVID-19 in dementia patients, the individuals that are at high risk of suffering from dementia and the potential acceleration of prion-like proteins spread following SARS-CoV-2 infection.
Keywords: Aged; COVID-19; Dementia; Humans; Neurodegenerative Diseases; Prions; SARS-CoV-2

Dementia Research on Facebook and Twitter: Current Practice and Challenges. - Hrincu, Viorica; An, Zijian; Joseph, Kenneth; Jiang, Yu Fei; Robillard, Julie M (J Alzheimers Dis, 2022)
BACKGROUND: Social media is a powerful tool for engaging diverse audiences in dementia research. However, there is little data summarizing current content exchange in this context. OBJECTIVE: To inform ethical dementia research engagement on social media, we characterized current practices by analyzing public social media posts. METHODS: We retrieved Facebook (2-year period, N = 7,896) and Twitter (1-year period, N = 9,323) posts containing dementia research-related keywords using manual and machine learning-based search strategies. We performed qualitative and quantitative content and sentiment analyses on random samples (10%) of the posts. RESULTS: Top Facebook users were advocacy (45%) and health organizations (25%). On Twitter, academics/researchers were the largest user group. Prevention was the most frequently coded theme (Facebook 30%; Twitter 26%), followed by treatment (Facebook 15%; Twitter 18%). Diagnostics had the highest Facebook engagement. Sharing knowledge was the primary form of content exchange (Facebook 63%; Twitter 80%). Most shared journal articles were peer-reviewed and open access. Emotional tone was overall more positive on Facebook. Justice was a prominent ethics topic regarding inequalities related to identity and intersecting modes of marginalization in dementia research. CONCLUSION: The findings indicate the importance of social media as an engagement tool of current topics in health research and reveal areas of potential for increased engagement. These data can inform consensus-based best practices for ethical social media application in dementia research.
Keywords: Dementia; Humans; Social Media

Demonstration of Clinical Meaningfulness of the Integrated Alzheimer's Disease Rating Scale (iADRS): Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes. - Wessels, Alette M; Belger, Mark; Johnston, Joseph A; Yu, Youying; Rentz, Dorene M; Dowsett, Sherie A; Chandler, Julie (J Alzheimers Dis, 2022)
BACKGROUND: The integrated Alzheimer's Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures. OBJECTIVE: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study. METHODS: Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition and/or function was the underlying explanation of any association between iADRS and health outcome change. RESULTS: Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life. CONCLUSION: Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression.
Keywords: Alzheimer Disease; Caregivers; Clinical Trials as Topic; Cognitive Dysfunction; Humans; Observational Studies as Topic; Outcome Assessment, Health Care; Quality of Life

Detecting Alzheimer's Disease Using Natural Language Processing of Referential Communication Task Transcripts. - Liu, Ziming; Paek, Eun Jin; Yoon, Si On; Casenhiser, Devin; Zhou, Wenjun; Zhao, Xiaopeng (J Alzheimers Dis, 2022)
BACKGROUND: People with Alzheimer's disease (AD) often demonstrate difficulties in discourse production. Referential communication tasks (RCTs) are used to examine a speaker's capability to select and verbally code the characteristics of an object in interactive conversation. OBJECTIVE: In this study, we used contextualized word representations from Natural language processing (NLP) to evaluate how well RCTs are able to distinguish between people with AD and cognitively healthy older adults. METHODS: We adapted machine learning techniques to analyze manually transcribed speech transcripts in an RCT from 28 older adults, including 12 with AD and 16 cognitively healthy older adults. Two approaches were applied to classify these speech transcript samples: 1) using clinically relevant linguistic features, 2) using machine learned representations derived by a state-of-art pretrained NLP transfer learning model, Bidirectional Encoder Representation from Transformer (BERT) based classification model. RESULTS: The results demonstrated the superior performance of AD detection using a designed transfer learning NLP algorithm. Moreover, the analysis showed that transcripts of a single image yielded high accuracies in AD detection. CONCLUSION: The results indicated that RCT may be useful as a diagnostic tool for AD, and that the task can be simplified to a subset of images without significant sacrifice to diagnostic accuracy, which can make RCT an easier and more practical tool for AD diagnosis. The results also demonstrate the potential of RCT as a tool to better understand cognitive deficits from the perspective of discourse production in people with AD.
Keywords: Aged; Alzheimer Disease; Cognitive Dysfunction; Communication; Humans; Natural Language Processing; Speech

Diabetic Retinopathy Predicts Risk of Alzheimer's Disease: A Danish Registry-Based Nationwide Cohort Study. - Pedersen, Frederik Nørregaard; Stokholm, Lonny; Pouwer, Frans; Hass Rubin, Katrine; Peto, Tunde; Frydkjær-Olsen, Ulrik; Thykjær, Anne Suhr; Andersen, Nis; Andresen, Jens; Bek, Toke; La Cour, Morten; Heegaard, Steffen; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD). OBJECTIVE: To investigate diabetes and DR as a risk marker of present and incident AD. METHODS: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. RESULTS: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59-0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81-0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08-1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18-1.53). CONCLUSION: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.
Keywords: Alzheimer Disease; Cohort Studies; Denmark; Diabetes Mellitus; Diabetic Retinopathy; Humans; Registries; Risk Factors

Digital Technologies to Prevent Social Isolation and Loneliness in Dementia: A Systematic Review. - Rai, Harleen Kaur; Kernaghan, David; Schoonmade, Linda; Egan, Kieren J; Pot, Anne Margriet (J Alzheimers Dis, 2022)
BACKGROUND: Dementia poses significant and sustained challenges to global society. Diagnosis can lead to increased feelings of loneliness and social isolation. People with dementia living alone are particularly at risk. Considering the growing number of technologies proposed to aid people with dementia address social isolation and loneliness, we reviewed the existing literature. OBJECTIVE: To collate and summarize current evidence for digital technologies to prevent social isolation and loneliness for people with dementia. METHODS: Following the PRISMA guidelines, we systematically searched five databases to identify studies of digital technologies designed to support or prevent social isolation or loneliness for people with dementia. Pre-specified outcomes included social isolation, loneliness, and quality of life. We used deductive thematic analysis to synthesize the major themes emerging from the studies. RESULTS: Ten studies met our inclusion criteria where all studies reported improvements in quality of life and seven reported benefits regarding social inclusion or a reduction in loneliness. Technologies were varied across purpose, delivery format, theoretical models, and levels of personalization. Two studies clearly described the involvement of people with dementia in the study design and five technologies were available outside the research context. CONCLUSION: There is limited- but increasing- evidence that technologies hold potential to improve quality of life and reduce isolation/loneliness for people with dementia. Results presented are largely based in small-scale research studies. Involvement of people with dementia was limited and few research concepts are reaching implementation. Closer collaboration with people with dementia to provide affordable, inclusive, and person-centered solutions is urgently required.
Keywords: Dementia; Digital Technology; Humans; Loneliness; Quality of Life; Social Isolation

Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer's Disease. - Sun, Xiaodi; Suo, Xinjun; Xia, Xianyou; Yu, Chunshui; Dou, Yan (J Alzheimers Dis, 2022)
BACKGROUND: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD. OBJECTIVE: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. METHODS: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. RESULTS: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition. CONCLUSION: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Cell Survival; Dimethyl Fumarate; Disease Models, Animal; Hippocampus; Inflammation; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Neurons; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Protective Agents; Reactive Oxygen Species

DNA Damage Increases Secreted Aβ40 and Aβ42 in Neuronal Progenitor Cells: Relevance to Alzheimer's Disease. - Welty, Starr; Thathiah, Amantha; Levine, Arthur Samuel (J Alzheimers Dis, 2022)
BACKGROUND: Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer's disease (AD). OBJECTIVE: To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation. METHODS: We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 and Aβ42. Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology. RESULTS: We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 h after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 h and 4 h after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons. CONCLUSION: These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD.

Does Loss of Integrity of the Cingulum Bundle Link Amyloid-β Accumulation and Neurodegeneration in Alzheimer's Disease? - Vlegels, Naomi; Ossenkoppele, Rik; van der Flier, Wiesje M; Koek, Huiberdina L; Reijmer, Yael D; Wisse, Laura Em; Biessels, Geert Jan (J Alzheimers Dis, 2022)
BACKGROUND: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. OBJECTIVE: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. METHODS: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. RESULTS: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. CONCLUSION: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.

Effect of Probiotic Bifidobacterium breve in Improving Cognitive Function and Preventing Brain Atrophy in Older Patients with Suspected Mild Cognitive Impairment: Results of a 24-Week Randomized, Double-Blind, Placebo-Controlled Trial. - Asaoka, Daisuke; Xiao, Jinzhong; Takeda, Tsutomu; Yanagisawa, Naotake; Yamazaki, Takahiro; Matsubara, Yoichiro; Sugiyama, Hideki; Endo, Noemi; Higa, Motoyuki; Kasanuki, Koji; Ichimiya, Yosuke; Koido, Shigeo; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Probiotics have been reported to ameliorate cognitive impairment. OBJECTIVE: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI). METHODS: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2×1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer's disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition. RESULTS: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale "orientation" was significantly improved compared to placebo at 24 weeks. MMSE subscales "orientation in time" and "writing" were significantly improved compared to placebo in the lower baseline MMSE (< 25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score ≥1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation. CONCLUSION: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects.
Keywords: Aged; Aged, 80 and over; Atrophy; Bifidobacterium breve; Brain; Cognition; Cognitive Dysfunction; Double-Blind Method; Humans; Probiotics

The Effectiveness of GRADIOR: A Neuropsychological Rehabilitation Program for People with Mild Cognitive Impairment and Mild Dementia. Results of a Randomized Controlled Trial After 4 and 12 Months of Treatment. - Diaz Baquero, Angie A; Franco-Martín, Manuel A; Parra Vidales, Esther; Toribio-Guzmán, José Miguel; Bueno-Aguado, Yolanda; Martínez Abad, Fernando; Perea Bartolomé, María V; Asl, Aysan Mahmoudi; van der Roest, Henriëtte G (J Alzheimers Dis, 2022)
BACKGROUND: Computer-based cognitive training programs have been developed with promising results on the maintenance/improvement of cognitive performance in people with dementia. OBJECTIVE: The objective was to evaluate the effectiveness of the cognitive rehabilitation program "GRADIOR" in people with mild cognitive impairment and mild dementia. METHOD: This study was a single-blind multicenter randomized clinical trial. Participants were recruited from hospitals/day centers. The experimental group (EG) and control group (CG) received computer-based cognitive training (CCT) and routine daily care, respectively. Outcome measures at T0: baseline, T1: at 4 months, T2: at 12 months were compared within and between-groups. RESULTS: Significant differences or important effect sizes were detected at the intragroup and intergroup level for most variables, observing a trend of improvement and/or maintenance at 4 months by Visual Reasoning of Cambridge Cognitive Examination (CAMCOG), Digit and Arithmetic of WAIS-III, Semantic Verbal Fluency, Mini-Mental State Exam (MMSE), Trail Making Test (TMT)-A-Mistakes and at 12 months by Visual Reasoning of CAMCOG, Digit Symbol of WAIS-III, TMT-B-mistakes, Visual Memory of Rivermead Behavioural Memory Test, Lexical Verbal Fluency-P, Yesavage's Geriatric Depression Scale (GDS), TMT-A-time scales whose objective was to evaluate some executive functions and/or the memory. The CG presented a worsening trend for most of the measures towards 12 months. There was also a significant interaction between "time and group" for MMSE (F = 8.971; p = 0.03; η 2 = 0.019) and the GDS (F = 3.414; p = 0.04; η 2 = 0.041), as well as small effect sizes for TMT-A-time (F = 1.641; p = 0.21; η 2 = 0.021) and TMT-A-mistakes (F = 0.908; p = 0.41; η 2 = 0.019). CONCLUSION: CCT with GRADIOR has been proved to benefit cognitive functions (ISRCTN:15742788).

Effects of a 6-Month Multifaceted Diet and Exercise Intervention on Cognition in Older Adults at Risk of Cognitive Decline: The PONDER Double-Blind, Placebo-Controlled Randomized Trial. - Macpherson, Helen; Brownell, Sarah; Harris, Elizabeth; Duckham, Rachel L; O'Connell, Stella; Meyer, Barbara J; Mirzaee, Sam; Daly, Robin M (J Alzheimers Dis, 2022)
BACKGROUND: Multidomain interventions which incorporate exercise and dietary supplementation to target both cognitive and physical health domains may be an important approach to delay cognitive decline. OBJECTIVE: The Protein Omega-3 aNd vitamin D Exercise Research (PONDER) study investigated the effects of a 6-month multifaceted intervention in community-dwelling older adults with subjective memory impairment on cognition (primary outcome), physical function, and body composition with a further 6-month follow up for cognition (secondary outcomes). METHODS: Single-center, community-based, parallel-group, randomized, double-blind placebo-controlled trial involving a 6-month multifaceted intervention with a further follow-up at 12 months. A total of 147 participants [mean age 70.2 years (SD 6.1), 70% female] were randomized to a multimodal exercise program consisting of twice-weekly supervised resistance and aerobic training, combined with a daily omega-3 (900 mg EPA, 600 mg DHA), vitamin D (1000 IU) and protein (20 g) supplement (n = 73), or a control condition (n = 74) comprising stretching/flexibility sessions combined with a placebo. The primary outcome was a composite CogState measure and Trail-Making Test B-A. RESULTS: There were no significant between-group differences in the change of cognition at 6 or 12 months or physical function outcomes at 6 months, but the intervention significantly improved total lean mass compared to controls [0.72 kg (95% CI 0.26-1.19), p = 0.001]. CONCLUSION: A multi-faceted intervention including an omega-3, vitamin D and protein-enriched supplement with twice-weekly exercise training did not provide any benefits to cognitive or physical function in older adults with subjective memory impairment, despite improvements in lean mass.

The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review. - Fan, Fangcheng; Liu, Hua; Shi, Xiaojie; Ai, Yangwen; Liu, Qingshan; Cheng, Yong (J Alzheimers Dis, 2022)
BACKGROUND: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse. OBJECTIVE: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients. METHODS: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles. RESULTS: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD. CONCLUSION: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.
Keywords: Activities of Daily Living; Alzheimer Disease; Amino Acids; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Ginkgo biloba; Humans; Nootropic Agents; Patient Safety; Plant Extracts; Rivastigmine

Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer's Disease, and Other Neurodegenerative Disorders. - Cutuli, Debora; Landolfo, Eugenia; Petrosini, Laura; Gelfo, Francesca (J Alzheimers Dis, 2022)
Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer's disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.
Keywords: Alzheimer Disease; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognition; Disease Models, Animal; Environment; Humans; Neurodegenerative Diseases; Neuronal Plasticity

Evaluation of the Accuracy of Cognitive Screening Tests in Detecting Dementia Associated with Alzheimer's Disease: A Hierarchical Bayesian Latent Class Meta-Analysis. - Wang, Xiaonan; Li, Fengjie; Gao, Qi; Jiang, Zhen; Abudusaimaiti, Xiayidanmu; Yao, Jiangyue; Zhu, Huiping (J Alzheimers Dis, 2022)
BACKGROUND: Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) are neuropsychological tests commonly used by physicians for screening cognitive dysfunction of Alzheimer's disease (AD). Due to different imperfect reference standards, the performance of MoCA and MMSE do not reach consensus. It is necessary to evaluate the consistence and differentiation of MoCA and MMSE in the absence of a gold standard for AD. OBJECTIVE: We aimed to assess the accuracy of MoCA and MMSE in screening AD without a gold standard reference test. METHODS: Studies were identified from PubMed, Web of Science, CNKI, Chinese Wanfang Database, China Science and Technology Journal Database, and Cochrane Library. Our search was limited to studies published in English and Chinese before August 2021. A hierarchical Bayesian latent class model was performed in meta-analysis when the gold standard was absent. RESULTS: A total of 67 studies comprising 5,554 individuals evaluated for MoCA and 76,862 for MMSE were included in this meta-analysis. The pooled sensitivity was 0.934 (95% CI 0.905 to 0.954) for MoCA and 0.883 (95% CI 0.859 to 0.903) for MMSE, while the pooled specificity was 0.899 (95% CI 0.859 to 0.928) for MoCA and 0.903 (95% CI 0.879 to 0.923) for MMSE. MoCA was useful to rule out dementia associated with AD with lower negative likelihood ratio (LR-) (0.074, 95% CI 0.051 to 0.108). MoCA showed better performance with higher diagnostic odds ratio (DOR) (124.903, 95% CI 67.459 to 231.260). CONCLUSION: MoCA had better performance than MMSE in screening dementia associated with AD from patients with mild cognitive impairment or healthy controls.
Keywords: Alzheimer Disease; Bayes Theorem; Cognition; Cognitive Dysfunction; Humans; Mental Status and Dementia Tests; Neuropsychological Tests

Evoked Cortical Depolarizations Before and After the Amyloid Plaque Accumulation: Voltage Imaging Study. - Zhu, Mei Hong; Jogdand, Aditi H; Jang, Jinyoung; Nagella, Sai C; Das, Brati; Milosevic, Milena M; Yan, Riqiang; Antic, Srdjan D (J Alzheimers Dis, 2022)
BACKGROUND: In Alzheimer's disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline. OBJECTIVE: Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings. METHODS: Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind. We developed an AD mouse model (APPswe/PS1dE9 background) expressing a genetically-encoded voltage indicator (GEVI) in the neocortex. GEVI was restricted to the excitatory pyramidal neurons (unlike the voltage-sensitive dyes). RESULTS: Expression of GEVI did not disrupt AD model formation of amyloid plaques. GEVI expression was stable in both AD model mice and Control (healthy) littermates (CTRL) over 247 days postnatal. Brain slices were stimulated in layer 2/3. From the evoked voltage waveforms, we extracted several parameters for comparison AD versus CTRL. Some parameters (e.g., temporal summation, refractoriness, and peak latency) were weak predictors, while other parameters (e.g., signal amplitude, attenuation with distance, and duration (half-width) of the evoked transients) were stronger predictors of the AD condition. Around postnatal age 150 days (P150) and especially at P200, synaptically-evoked voltage signals in brain slices were weaker in the AD groups versus the age- and sex-matched CTRL groups, suggesting an AD-mediated synaptic weakening that coincides with the accumulation of plaques. However, at the youngest ages examined, P40 and P80, the AD groups showed differentially stronger signals, suggesting "hyperexcitability" prior to the formation of plaques. CONCLUSION: Our results indicate bidirectional alterations in cortical physiology in AD model mice; occurring both prior (P40-80), and after (P150-200) the amyloid deposition.

Excretion of Amyloid-β in the Gastrointestinal Tract and Regulation by the Gut Microbiota. - Wu, Shijing; Hu, Li; Lin, Jiajing; Li, Kanglan; Ye, Shicai; Zhu, Shaoping; Liu, Zhou (J Alzheimers Dis, 2022)
BACKGROUND: Amyloid-β (Aβ) is important in the etiology of Alzheimer's disease (AD). Removal of Aβ from the brain is a major strategy for the prevention and treatment of AD. OBJECTIVE: To clarify whether Aβ 42 can be cleared by intestinal excretion and whether the gut microbiota (GM) can affect the excretory clearance of Aβ 42 in the peripheral blood and intestines. METHODS: Male 8-month-old C57BL6 mice were maintained on either normal chow or received broad-spectrum antibiotics in their drinking water for one week. Sterile saline, fluorescein isothiocyanate (FITC), or FITC-Aβ 42 (fluorescein isothiocyanate-labeled amyloid-β 42 peptides) was injected 1 h before FITC, or FITC-Aβ 42 was injected 1 h before sampling. Related changes of Aβ 42 before and after injection were evaluated. RESULTS: FITC-Aβ 42 was injected into mice through the tail vein and could later be detected in feces. Furthermore, the fecal concentrations of FITC-Aβ 42 were higher in mice that had been fed antibiotics to alter their GM than in normal mice. However, the FITC-Aβ 42 concentrations in blood showed the opposite pattern. CONCLUSION: Aβ 42 can be excreted into the intestinal lumen and is regulated by the GM.

Expression Changes in Mitochondrial Genes Affecting Mitochondrial Morphology, Transmembrane Potential, Fragmentation, Amyloidosis, and Neuronal Cell Death Found in Brains of Alzheimer's Disease Patients. - Castora, Frank J; Kerns, Kimberly A; Pflanzer, Haley K; Hitefield, Naomi L; Gershon, Blake; Shugoll, Jason; Shelton, Morgan; Coleman, Randolph A (J Alzheimers Dis, 2022)
BACKGROUND: Alzheimer's disease (AD) is a neurological disease that has both a genetic and non-genetic origin. Mitochondrial dysfunction is a critical component in the pathogenesis of AD as deficits in oxidative capacity and energy production have been reported. OBJECTIVE: Nuclear-encoded mitochondrial genes were studied in order to understand the effects of mitochondrial expression changes on mitochondrial function in AD brains. These expression data were to be incorporated into a testable mathematical model for AD used to further assess the genes of interest as therapeutic targets for AD. METHODS: RT2-PCR arrays were used to assess expression of 84 genes involved in mitochondrial biogenesis in AD brains. A subset of mitochondrial genes of interest was identified after extensive Ingenuity Pathway Analysis (IPA) (Qiagen). Further filtering of this subset of genes of interest was achieved by individual qPCR analyses. Expression values from this group of genes were included in a mathematical model being developed to identify potential therapeutic targets. RESULTS: Nine genes involved in trafficking proteins to mitochondria, morphology of mitochondria, maintenance of mitochondrial transmembrane potential, fragmentation of mitochondria and mitochondrial dysfunction, amyloidosis, and neuronal cell death were identified as significant to the changes seen. These genes include TP53, SOD2, CDKN2A, MFN2, DNM1L, OPA1, FIS1, BNIP3, and GAPDH. CONCLUSION: Altered mitochondrial gene expression indicates that a subset of nuclear-encoded mitochondrial genes compromise multiple aspects of mitochondrial function in AD brains. A new mathematical modeling system may provide further insights into potential therapeutic targets.

Frontal Atrophy and Executive Dysfunction Relate to Complex Numbers Impairment in Progressive Supranuclear Palsy. - Howard, Erica; Ballinger, Samantha; Kinney, Nikolas G; Balgenorth, Yvonne; Ehrhardt, Annabess; Phillips, Jeffrey S; Irwin, David J; Grossman, Murray; Cousins, Katheryn A Q (J Alzheimers Dis, 2022)
BACKGROUND: Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday tasks may help elucidate neurocognitive and neuroanatomic bases of numbers deficits in PS. OBJECTIVE: To test neurocognitive and neuroanatomic correlates of complex numerical processing in PS, we assessed number abilities, neuropsychological performance, and cortical thickness in progressive supranuclear palsy (PSP) and Lewy body spectrum disorders (LBSD). METHODS: Fifty-six patients (LBSD = 35; PSP = 21) completed a Numbers Battery, including basic and complex numerical tasks. The Mini-Mental State Exam (MMSE), letter fluency (LF), and Judgment of Line Orientation (JOLO) assessed global, executive, and visuospatial functioning respectively. Mann-Whitney U tests compared neuropsychological testing and rank-transformed analysis of covariance (ANCOVA) compared numbers performance between groups while adjusting for demographic variables. Spearman's and partial correlations related numbers performance to neuropsychological tasks. Neuroimaging assessed cortical thickness in disease groups and demographically-matched healthy controls. RESULTS: PSP had worse complex numbers performance than LBSD (F = 6.06, p = 0.02) but similar basic numbers performance (F = 0.38, p >  0.1), covarying for MMSE and sex. Across syndromes, impaired complex numbers performance was linked to poor LF (rho = 0.34, p = 0.01) but not JOLO (rho = 0.23, p >  0.05). Imaging revealed significant frontal atrophy in PSP compared to controls, which was associated with worse LF and complex numbers performance. CONCLUSION: PSP demonstrated selective impairments in complex numbers processing compared to LBSD. This complex numerical deficit may relate to executive dysfunction and frontal atrophy.

Functional Neurophysiological Biomarkers of Early-Stage Alzheimer's Disease: A Perspective of Network Hyperexcitability in Disease Progression. - Tok, Sean; Ahnaou, Abdallah; Drinkenburg, Wilhelmus (J Alzheimers Dis, 2022)
Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological indicator of Alzheimer's disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential indicator of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this readout. Several hypotheses have been put forward to explain the prevalence of NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomarkers; Disease Progression; Humans; Nervous System Physiological Phenomena; Neurophysiology; tau Proteins

Glucometabolic Changes Are Associated with Structural Gray Matter Alterations in Prodromal Dementia. - Gentreau, Mélissa; Reynes, Christelle; Sabatier, Robert; Maller, Jerome J; Meslin, Chantal; Deverdun, Jeremy; Le Bars, Emmanuelle; Raymond, Michel; Berticat, Claire; Artero, Sylvaine (J Alzheimers Dis, 2022)
BACKGROUND: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer's disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated. OBJECTIVE: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia. METHODS: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants during the 7-year follow-up) were identified using a data-driven machine learning algorithm. RESULTS: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes. CONCLUSION: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology.

High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations. - Sturchio, Andrea; Dwivedi, Alok K; Malm, Tarja; Wood, Matthew J A; Cilia, Roberto; Sharma, Jennifer S; Hill, Emily J; Schneider, Lon S; Graff-Radford, Neill R; Mori, Hiroshi; Nübling, Georg; El Andaloussi, Samir; et al. (J Alzheimers Dis, 2022)
BACKGROUND: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. OBJECTIVE: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). METHODS: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. RESULTS: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8% ) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. CONCLUSION: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24. - Hu, Li-Tian; Xie, Xiao-Yong; Zhou, Gui-Feng; Wen, Qi-Xin; Song, Li; Luo, Biao; Deng, Xiao-Juan; Pan, Qiu-Ling; Chen, Guo-Jun (J Alzheimers Dis, 2022)
BACKGROUND: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. OBJECTIVE: The present study was to investigate the role of HMGCS2 in Tau/p degradation. METHODS: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. RESULTS: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. CONCLUSION: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

Impact of COVID-19 on 'Living Well' with Mild-to-Moderate Dementia in the Community: Findings from the IDEAL Cohort. - Clare, Linda; Martyr, Anthony; Gamble, Laura D; Pentecost, Claire; Collins, Rachel; Dawson, Eleanor; Hunt, Anna; Parker, Sophie; Allan, Louise; Burns, Alistair; Hillman, Alexandra; Litherland, Rachael; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Negative impacts of the COVID-19 pandemic on people with dementia have been widely-documented, but most studies have relied on carer reports and few have compared responses to information collected before the pandemic. OBJECTIVE: We aimed to explore the impact of the pandemic on community-dwelling individuals with mild-to-moderate dementia and compare responses with pre-pandemic data. METHODS: During the second wave of the pandemic, we conducted structured telephone interviews with 173 people with dementia and 242 carers acting as informants, all of whom had previously participated in the IDEAL cohort. Where possible, we benchmarked responses against pre-pandemic data. RESULTS: Significant perceived negative impacts were identified in cognitive and functional skills and ability to engage in self-care and manage everyday activities, along with increased levels of loneliness and discontinuity in sense of self and a decline in perceived capability to 'live well'. Compared to pre-pandemic data, there were lower levels of pain, depression, and anxiety, higher levels of optimism, and better satisfaction with family support. There was little impact on physical health, mood, social connections and relationships, or perceptions of neighborhood characteristics. CONCLUSION: Efforts to mitigate negative impacts of pandemic-related restrictions and restore quality of life could focus on reablement to address the effects on participation in everyday activities, creating opportunities for social contact to reduce loneliness, and personalized planning to reconnect people with their pre-COVID selves. Such efforts may build on the resilience demonstrated by people with dementia and carers in coping with the pandemic.
Keywords: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Caregivers; COVID-19; Dementia; Female; Humans; Male; Middle Aged; Neighborhood Characteristics; Quality of Life; SARS-CoV-2

Impaired Experience-Dependent Refinement of Place Cells in a Rat Model of Alzheimer's Disease. - Broussard, John I; Redell, John B; Maynard, Mark E; Zhao, Jing; Moore, Anthony; Mills, Rachel W; Hood, Kimberly N; Underwood, Erica; Roysam, Badrinath; Dash, Pramod K (J Alzheimers Dis, 2022)
BACKGROUND: Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer's disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells. OBJECTIVE: To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties. METHODS: We implanted 32-channel electrode arrays into the CA1 subfield of 18-month-old male WT and TgF344-AD (n = 6/group) rats. Ten days after implantation, single unit activity in an open field arena was recorded across days. The spatial information content, in-field firing rate, and stability of each place cell was compared across groups. Pathology was assessed by immunohistochemical staining, and a deep neural network approach was used to count cell profiles. RESULTS: Aged TgF344-AD rats exhibited hippocampal amyloid-β deposition, and a significant increase in Iba1 immunoreactivity and microglia cell counts. Place cells from WT and TgF344-AD rat showed equivalent spatial information, in-field firing rates, and place field stability when initially exposed to the arena. However, by day 3, the place cells in aged WT rats showed characteristic spatial tuning as evidenced by higher spatial information content, stability, and in-field firing rates, an effect not seen in TgF344-AD rats. CONCLUSION: These findings support the notion that altered electrophysiological properties of place cells may contribute to the learning and memory deficits observed in AD.

Importance of Accounting for Regional Differences in Modifiable Risk Factors for Alzheimer's Disease and Related Dementias: The Case for Tailored Interventions. - Hoffmann, Coles M; Nianogo, Roch A; Yaffe, Kristine; Rosenwohl-Mack, Amy; Carrasco, Anna; Barnes, Deborah E (J Alzheimers Dis, 2022)
BACKGROUND: We recently estimated that 36.9% of Alzheimer's disease and related dementias (ADRD) cases in the US may be attributable to modifiable risk factors, but it is not known whether national estimates generalize to specific states or regions. OBJECTIVE: To compare national estimates of modifiable risk factors of ADRD to California, overall and by sex and race/ethnicity, and to estimate number of cases potentially preventable by reducing the prevalence of key risk factors by 25%. METHODS: Adults ≥18 years who participated in the Behavioral Risk Factor Surveillance Survey in California (n = 9,836) and the US (n = 378,615). We calculated population attributable risks (PARs) for eight risk factors (physical inactivity, current smoking, depression, low education, diabetes mellitus, midlife obesity, midlife hypertension, and hearing loss) and compared estimates in California and the U.S. RESULTS: In California, overall, 28.9% of ADRD cases were potentially attributable to the combination of risk factors, compared to 36.9% in the U.S. The top three risk factors were the same in California and the U.S., although their relative importance differed (low education [CA:14.9%; U.S.:11.7% ], midlife obesity [CA:14.9%; U.S.:17.7% ], and physical inactivity [CA:10.3%; U.S.:11.8% ]). The number of ADRD cases attributable to the combined risk factors was 199,246 in California and 2,287,683 in the U.S. If the combined risk factors were reduced by 25%, we could potentially prevent more than 40,000 cases in California and 445,000 cases in the U.S. CONCLUSION: Our findings highlight the importance of examining risk factors of ADRD regionally, and within sex and race/ethnic groups to tailor dementia risk reduction strategies.

Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study. - Laton, Jorne; Van Schependom, Jeroen; Goossens, Joery; Wiels, Wietse; Sieben, Anne; De Deyn, Peter Paul; Goeman, Johan; Streffer, Johannes; van der Zee, Julie; Martin, Jean-Jacques; Van Broeckhoven, Christine; De Vos, Maarten; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy. OBJECTIVE: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis. METHODS: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG). RESULTS: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95% . Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. CONCLUSION: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools.

Improved Prediction of Amyloid-β and Tau Burden Using Hippocampal Surface Multivariate Morphometry Statistics and Sparse Coding. - Wu, Jianfeng; Su, Yi; Zhu, Wenhui; Jalili Mallak, Negar; Lepore, Natasha; Reiman, Eric M; Caselli, Richard J; Thompson, Paul M; Chen, Kewei; Wang, Yalin (J Alzheimers Dis, 2022)
BACKGROUND: Amyloid-β (Aβ) plaques and tau protein tangles in the brain are the defining 'A' and 'T' hallmarks of Alzheimer's disease (AD), and together with structural atrophy detectable on brain magnetic resonance imaging (MRI) scans as one of the neurodegenerative ('N') biomarkers comprise the "ATN framework" of AD. Current methods to detect Aβ/tau pathology include cerebrospinal fluid (invasive), positron emission tomography (PET; costly and not widely available), and blood-based biomarkers (promising but mainly still in development). OBJECTIVE: To develop a non-invasive and widely available structural MRI-based framework to quantitatively predict the amyloid and tau measurements. METHODS: With MRI-based hippocampal multivariate morphometry statistics (MMS) features, we apply our Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP) method combined with the ridge regression model to individual amyloid/tau measure prediction. RESULTS: We evaluate our framework on amyloid PET/MRI and tau PET/MRI datasets from the Alzheimer's Disease Neuroimaging Initiative. Each subject has one pair consisting of a PET image and MRI scan, collected at about the same time. Experimental results suggest that amyloid/tau measurements predicted with our PASCP-MP representations are closer to the real values than the measures derived from other approaches, such as hippocampal surface area, volume, and shape morphometry features based on spherical harmonics. CONCLUSION: The MMS-based PASCP-MP is an efficient tool that can bridge hippocampal atrophy with amyloid and tau pathology and thus help assess disease burden, progression, and treatment effects.

Incidence and Outcomes of SARS-CoV-2 Infection in Older Adults Living with Dementia: A Population-Based Cohort Study. - Cascini, Silvia; Agabiti, Nera; Marino, Claudia; Acampora, Anna; Balducci, Maria; Calandrini, Enrico; Davoli, Marina; Bargagli, Anna Maria (J Alzheimers Dis, 2022)
BACKGROUND: The identification of risk factors for SARS-CoV-2 infection and mortality in patients with dementia is a key aspect to support clinical decisions and public health interventions. OBJECTIVE: To assess the incidence of SARS-CoV-2 infection and COVID-19 related death in a cohort of patients with dementia residing in the Lazio region and to investigate predicting factors for both infection and mortality. METHODS: This population-based study used information from administrative databases and the SARS-CoV-2 infection surveillance system. Patients with dementia (age ≥65) were enrolled as of December 31, 2019 and followed-up until February 28, 2021. Cumulative risk of infection and death within 60 days of infection onset, and age-standardized incidence (SIR) and mortality (SMR) ratios were calculated. Logistic regression models were applied to identify factors associated with infection and mortality. RESULTS: Among 37,729 dementia patients, 2,548 had a diagnosis of SARS-CoV-2 infection. The crude risk of infection was 6.7% . An increase in risk of infection was observed both in women (SIR 1.72; 95% CI 1.64-1.80) and men (SIR 1.43; 95% CI 1.33-1.54). Pneumonia, cerebrovascular and blood diseases, femur fracture, anxiety, antipsychotic and antithrombotic use were associated with an increased risk of infection. The crude risk of death was 31.0%, the SMRs 2.32 (95% CI 2.05-2.65) for men, and 2.82 (95% CI 2.55-3.11) for women. Factors associated with mortality included: male gender, age ≥85, symptoms at the diagnosis, antipsychotic and systemic antibiotics treatment. CONCLUSION: These findings emphasize the need of close and tailored monitoring of dementia patients to reduce the impact of COVID-19 on this fragile population.

Increased Functional Connectivity of the Precuneus in Individuals with a Family History of Alzheimer's Disease. - Green, Zachary D; Vidoni, Eric D; Swerdlow, Russell H; Burns, Jeffrey M; Morris, Jill K; Honea, Robyn A (J Alzheimers Dis, 2022)
BACKGROUND: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. OBJECTIVE: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk. METHODS: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions. RESULTS: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions. CONCLUSION: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

Informal Caregivers' Attitude Toward Dementia: The Impact of Dementia Knowledge, Confidence in Dementia Care, and the Behavioral and Psychological Symptoms of the Person with Dementia. A Cross-Sectional Study. - Teichmann, Birgit; Gkioka, Mara; Kruse, Andreas; Tsolaki, Magda (J Alzheimers Dis, 2022)
BACKGROUND: Dementia is rapidly increasing worldwide due to demographic aging. More than two-thirds of patients are cared by family members. The quality of care depends on the caregivers' attitude toward dementia influencing patient care decisions. OBJECTIVE: The aim of this study is to examine the factors that influence the caregivers' attitude and whether there is an association between participation in a psycho-educational program and attitude. METHODS: We performed a cross-sectional study using a structured closed-ended questionnaire to retrieve socio-demographic information from caregivers and the persons with dementia (N = 86). The study included validated scales such as the Dementia Attitude Scale, the Dementia Knowledge Assessment Tool 2, the Positive Aspects of Caregiving, the Zarit Burden Interview, the Confidence in Dementia Scale, and Spielberger's State-Trait Anxiety Inventory, as well as a neuropsychological battery to assess the condition of people with dementia. RESULTS: Our final model explains 55.6% of the total variance and shows a significant correlation of five factors with attitude toward dementia: confidence, behavioral and psychological symptoms of dementia, anxiety as a trait, positive aspects of caregiving, and dementia knowledge. The caregivers who participated in a psycho-educational program showed a significantly more positive attitude toward dementia, better dementia knowledge, higher confidence in dementia care, and lower anxiety as a state. CONCLUSION: The strong correlation of attitude and knowledge, as well as confidence in dementia care, supports the tripartite model of attitude, which hypothesizes the interrelation of affect, cognition, and behavior.
Keywords: Attitude; Caregivers; Cross-Sectional Studies; Dementia; Humans; Surveys and Questionnaires

Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults. - Wittfeld, Katharina; Raman, Mekala R; Conner, Sarah C; Aslam, Asra; Teumer, Alexander; Nauck, Matthias; Hosten, Norbert; Habes, Mohamad; DeCarli, Charles; Vasan, Ramachandran S; Beiser, Alexa S; Himali, Jayandra J; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. OBJECTIVE: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. METHODS: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. RESULTS: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. CONCLUSION: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

Integrating the Synergy of the Gut Microbiome into Regenerative Medicine: Relevance to Neurological Disorders. - Preethy, Senthilkumar; Ranganathan, Natarajan; Raghavan, Kadalraja; Dedeepiya, Vidyasagar Devaprasad; Ikewaki, Nobunao; Abraham, Samuel J K (J Alzheimers Dis, 2022)
A new paradigm of cell therapy-based approaches as a solution to several diseases caused by damage or loss of cells/tissues leading to organ failure heralded the birth of a new branch in medicine called regenerative medicine (RM), which was further fueled by in vitro cell expansion and tissue engineering (TE) technologies, including the ability to grow embryonic stem cells, induce pluripotent stem cells, and so on. RM addresses organ failure by repair, regeneration, or restoration, rejuvenation using cells, stem cells, or progenitor cells as tools having added cell-derived products also as a tool, and extracellular matrix component-based support, either direct or indirect (e.g., matrix induced autologous chondrocyte implantation) using scaffolds. Now, the main objective of RM is to solve the functional loss of cells that have evolved from cells as tools to cell-derived factors and scaffolds per se as tools. In this context, an important yet indispensable group of cells that constitute the major portion of the human body in terms of the number of cells having several essential roles to play, both directly and indirectly, starting from digestion and the immune system to the growing evidence of influencing neuronal function, aging, and carcinogenesis has been ignored. We would like to focus on these in this review as they should essentially be considered as a tool of RM, especially for neurological disorders for their vital role. What we are indicating is the second genome or the gut microbiome.
Keywords: Gastrointestinal Microbiome; Humans; Nervous System Diseases; Regenerative Medicine; Stem Cells; Tissue Engineering

Interaction Between Diet and Microbiota in the Pathophysiology of Alzheimer's Disease: Focus on Polyphenols and Dietary Fibers. - Ticinesi, Andrea; Mancabelli, Leonardo; Carnevali, Luca; Nouvenne, Antonio; Meschi, Tiziana; Del Rio, Daniele; Ventura, Marco; Sgoifo, Andrea; Angelino, Donato (J Alzheimers Dis, 2022)
Animal studies increasingly indicate that the gut microbiota composition and function can be involved in the pathophysiology and progression of Alzheimer's disease (AD) at multiple levels. However, few studies have investigated this putative gut-brain axis in human beings, and none of them considered diet as a determinant of intestinal microbiota composition. Epidemiological studies highlight that a high intake of fruit and vegetables, such as that typical of the Mediterranean diet, can modulate AD progression. Thus, nutritional interventions are being increasingly studied as a possible non-pharmacological strategy to slow down the progression of AD. In particular, polyphenols and fibers represent the nutritional compounds with the higher potential of counterbalancing the pathophysiological mechanisms of dementia due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. These actions are mediated by the gut microbiota, that can transform polyphenols and fibers into biologically active compounds including, among others, phenyl-γ-valerolactones, urolithins, butyrate, and other short-chain fatty acids. In this review, the complex mechanisms linking nutrition, gut microbiota composition, and pathophysiology of cognitive decline in AD are discussed, with a particular focus on the role of polyphenols and fibers. The gaps between pre-clinical and clinical studies are particularly emphasized, as well as the urgent need for studies comprehensively evaluating the link between nutrition, microbiome, and clinical aspects of AD.
Keywords: Alzheimer Disease; Animals; Diet; Diet, Mediterranean; Dietary Fiber; Humans; Microbiota; Polyphenols

Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study. - Ning, Jing; Huang, Shu-Yi; Chen, Shi-Dong; Zhang, Ya-Ru; Huang, Yu-Yuan; Yu, Jin-Tai (J Alzheimers Dis, 2022)
BACKGROUND: Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. OBJECTIVE: Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. METHODS: We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. RESULTS: Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. CONCLUSION: Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.
Keywords: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Gastrointestinal Microbiome; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Neurodegenerative Diseases; Parkinson Disease; Risk Factors; Serotonin

Investigating Causal Relations Between Circulating Metabolites and Alzheimer's Disease: A Mendelian Randomization Study. - Huang, Shu-Yi; Yang, Yu-Xiang; Zhang, Ya-Ru; Kuo, Kevin; Li, Hong-Qi; Shen, Xue-Ning; Chen, Shi-Dong; Chen, Ke-Liang; Dong, Qiang; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2022)
BACKGROUND: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer's disease (AD). However, the causal relationships between metabolism and AD are poorly understood. OBJECTIVE: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. METHODS: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. RESULTS: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52-6.66, p = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05-1.39, p = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41-5.30, p = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53-3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71-0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. CONCLUSION: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.
Keywords: Alzheimer Disease; Apolipoproteins B; Cholesterol; Genome-Wide Association Study; Glutamine; Humans; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors

An Investigation into the Effects of Outer Membrane Vesicles and Lipopolysaccharide of Porphyromonas gingivalis on Blood-Brain Barrier Integrity, Permeability, and Disruption of Scaffolding Proteins in a Human in vitro Model. - Pritchard, Anna Barlach; Fabian, Zsolt; Lawrence, Clare L; Morton, Glyn; Crean, StJohn; Alder, Jane E (J Alzheimers Dis, 2022)
BACKGROUND: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB). OBJECTIVE: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a primary-derived human model representing the neurovascular unit of the BBB. METHODS: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy. RESULTS: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls. CONCLUSION: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains).

Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients. - Assogna, Martina; Motta, Caterina; Bonní, Sonia; Borghi, Ilaria; Casula, Elias P; Martorana, Alessandro; Koch, Giacomo (J Alzheimers Dis, 2022)
BACKGROUND: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients. OBJECTIVE: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype. METHODS: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of Aβ amyloid deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination scores respect to the baseline. RESULTS: A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p <  0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (-0.5±2.12 versus -6.05±4.95; post-hoc p = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p >  0.05). CONCLUSION: Our results suggest that APOE4 in patients with isolated amyloid pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

It's Groundhog Day! What Can the History of Science Say About the Crisis in Alzheimer's Disease Research? - Jacobs, Noortje; Theunissen, Bert (J Alzheimers Dis, 2022)
For years now, Alzheimer's disease (AD) research has been stuck in a Groundhog-Day scenario: an endless time loop with no breakthrough in sight. Disagreement about the validity of the field's dominant approach, based on the Amyloid Cascade Hypothesis, has led to a seemingly unresolvable trench war between proponents and critics. Our paper evaluates the recent scientific literature on AD from a historical and philosophical perspective. We show that AD research is a classic example of the boundary work at play in a field in crisis: both parties deploy historical and philosophical references to illustrate what counts as good and bad science, as proper scientific method and appropriate scientific conduct. We also show that boundary work has proved unable to point a way out of the deadlock and argue that the science system's tools for establishing scientific quality, such as peer review and the grant system, are unlikely to resolve the crisis. Rather, they consolidate the dominant model's position even more. In conclusion, we suggest that some kind of reverse boundary-work is needed that reopens the discussion on the nature of AD, an issue that has never been settled scientifically. Drawing on historical and philosophical work, we make clear that the definition of AD as a biomedical disease for which a cure can be found has consequences, not only for funding opportunities, but also for patients and their lives. A reconsideration of the desirability of these consequences may lead to different choices with respect to research priorities and patient care.
Keywords: Alzheimer Disease; Amyloid; Humans

Late-Onset Alcohol Abuse as a Presenting Symptom of Neurodegenerative Diseases. - de Paula França Resende, Elisa; Ketelle, Robin; Karydas, Anna; Allen, Isabel; Grinberg, Lea T; Spina, Salvatore; Seeley, William W; Perry, David C; Miller, Bruce; Naasan, Georges (J Alzheimers Dis, 2022)
BACKGROUND: The association between lifetime alcohol abuse and a higher risk to develop dementia is well known. However, it is unknown whether older adults who begin abusing alcohol late in life have an underlying neurodegenerative disease. OBJECTIVE: Identify the frequency of lifelong alcohol abuse (L-AA), late-onset alcohol abuse (LO-AA), and alcohol abuse as a first symptom of dementia (AA-FS) in patients with neurodegenerative diseases. METHODS: Cross-sectional retrospective study of patients evaluated at an academic referral center with a clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD), Alzheimer-type dementia (AD), and semantic variant primary progressive aphasia (svPPA) (n = 1,518). The presence of alcohol abuse was screened with the National Alzheimer's Coordinating Center questionnaire. L-AA was defined as onset <  40 years, LO-AA as onset ≥40 years, and AA-FS was defined when the abuse started within the first three years from symptom onset. RESULTS: The frequency of LO-AA was 2.2% (n = 33/1,518). LO-AA was significantly more frequent in patients with bvFTD than AD (7.5%, n = 13/173 versus 1.3%, n = 16/1,254, CI:1.0;11.4%), but not svPPA (4.4%, n = 4/91, CI: -4.4;10.7%). Similarly, AA-FS was more frequent in bvFTD patients than AD (5.7%, n = 10/173 versus 0.7%, n = 9/1,254, CI:0.5% ;9.5%), but not svPPA (2.2%, n = 2/91, CI:-2.4;9.1%). CONCLUSION: LO-AA can be a presenting symptom of dementia, especially bvFTD. Alcohol abuse onset later in life should prompt a clinical investigation into the possibility of an underlying neurodegenerative process because delay in diagnosis and treatment may increase patient and caregiver burden. The results need to be interpreted with caution due to the limitations of the study.

Lipid Peroxidation as a Marker of Apathy and Executive Dysfunction in Patients at Risk for Vascular Cognitive Impairment. - Bawa, Kritleen K; Ba, Joycelyn; Kiss, Alex; Wang, RuoDing; Feng, Vivian; Swardfager, Walter; Andreazza, Ana; Gallagher, Damien; Marotta, Giovanni; Herrmann, Nathan; Lanctôt, Krista L (J Alzheimers Dis, 2022)
BACKGROUND: The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown. OBJECTIVE: This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI. METHODS: In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated. RESULTS: Participants (n = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p <  0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤-1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t = 4.852, p <  0.001) and executive function (B(SE) = -0.19 (0.079), t = -2.377, p = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t = 3.149, p = 0.002). CONCLUSION: The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI.

Lipid Rafts Act as a Common Platform for Amyloid-β Oligomer-Induced Alzheimer's Disease Pathology. - Kawarabayashi, Takeshi; Nakamura, Takumi; Sato, Kaoru; Seino, Yusuke; Ichii, Sadanobu; Nakahata, Naoko; Takatama, Masamitsu; Westaway, David; George-Hyslop, Peter St; Shoji, Mikio (J Alzheimers Dis, 2022)
BACKGROUND: Amyloid-β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer's disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. OBJECTIVE: We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. METHODS: Cellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. RESULTS: Aβ dimers, the cellular prion protein (PrPc), and Aβ dimer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ dimer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice. CONCLUSION: Lipid rafts act as a common platform for the progression of AD pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.

Longitudinal Changes in Resting-State Functional Connectivity and Gray Matter Volume Are Associated with Conversion to Hearing Impairment in Older Adults. - Fitzhugh, Megan C; Pa, Judy (J Alzheimers Dis, 2022)
BACKGROUND: Hearing loss was recently identified as a modifiable risk factor for dementia although the potential mechanisms explaining this relationship are unknown. OBJECTIVE: The current study examined longitudinal change in resting-state fMRI functional connectivity and gray matter volume in individuals who developed a hearing impairment compared to those whose hearing remained normal. METHODS: This study included 440 participants from the UK Biobank: 163 who had normal hearing at baseline and impaired hearing at follow-up (i.e., converters, mean age = 63.11±6.33, 53% female) and 277 who had normal hearing at baseline and maintained normal hearing at follow-up (i.e., non-converters, age = 63.31±5.50, 50% female). Functional connectivity was computed between a priori selected auditory seed regions (left and right Heschl's gyrus and cytoarchitectonic subregions Te1.0, Te1.1, and Te1.2) and select higher-order cognitive brain networks. Gray matter volume within these same regions was also obtained. RESULTS: Converters had increased connectivity from left Heschl's gyrus to left anterior insula and from right Heschl's gyrus to right anterior insula, and decreased connectivity between right Heschl's gyrus and right hippocampus, compared to non-converters. Converters also had reduced gray matter volume in left hippocampus and left lateral visual cortex compared to non-converters. CONCLUSION: These findings suggest that conversion to a hearing impairment is associated with altered brain functional connectivity and gray matter volume in the attention, memory, and visual processing regions that were examined in this study.

Low-Dose Radiation Therapy Reduces Amyloid Load in Young 3xTg-AD Mice. - Ceyzériat, Kelly; Tournier, Benjamin B; Millet, Philippe; Dipasquale, Giovanna; Koutsouvelis, Nikolaos; Frisoni, Giovanni B; Garibotto, Valentina; Zilli, Thomas (J Alzheimers Dis, 2022)
BACKGROUND: Low-dose radiation therapy (LD-RT) has been shown to decrease amyloidosis or inflammation in systemic diseases and has recently been proposed as possible treatment of Alzheimer's disease (AD). A positive effect of LD-RT on tauopathy, the other marker of AD, has also been suggested. These effects have been shown in preclinical studies, but their mechanisms are still not well understood. OBJECTIVE: This study aimed to evaluate if anti-amyloid and anti-inflammatory effects of LD-RT can be observed at an early stage of the disease. Its impact on tauopathy and behavioral alterations was also investigated. METHODS: The whole brain of 12-month-old 3xTg-AD mice was irradiated with 10 Gy in 5 daily fractions of 2 Gy. Mice underwent behavioral tests before and 8 weeks post treatment. Amyloid load, tauopathy, and neuroinflammation were measured using histology and/or ELISA. RESULTS: Compared with wild-type animals, 3xTg-AD mice showed a moderate amyloid and tau pathology restricted to the hippocampus, a glial reactivity restricted to the proximity of amyloid plaques. LD-RT significantly reduced Aβ 42 aggregated forms (-71%) in the hippocampus and tended to reduce other forms in the hippocampus and frontal cortex but did not affect tauopathy or cognitive performance. A trend for neuroinflammation markers reduction was also observed. CONCLUSION: When applied at an early stage, LD-RT reduced amyloid load and possibly neuroinflammation markers, with no impact on tauopathy. The long-term persistence of these beneficial effects of LD-RT should be evaluated in future studies.

Medial Temporal Atrophy in Posterior Cortical Atrophy and Its Relationship to the Cingulate Island Sign. - Josephs, Kennedy A; Pham, Nha Trang Thu; Graff-Radford, Jonathan; Machulda, Mary M; Lowe, Val J; Whitwell, Jennifer L (J Alzheimers Dis, 2022)
BACKGROUND: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA). OBJECTIVE: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing. METHODS: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. RESULTS: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS. CONCLUSION: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.
Keywords: Alzheimer Disease; Atrophy; Fluorodeoxyglucose F18; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Positron-Emission Tomography

Metabolic Factors Are Related to Brain Amyloid Among Mexican Americans: A HABS-HD Study. - O'Bryant, Sid E; Petersen, Melissa; Hall, James; Johnson, Leigh (J Alzheimers Dis, 2022)
BACKGROUND: Despite the tremendous amount of research on Alzheimer's disease (AD) biomarkers, very little data is available regarding the fundamental biomarkers of AD among Mexican Americans. OBJECTIVE: Here we sought to examine the link between metabolic markers and brain amyloid among Mexican Americans as compared to non-Hispanic whites from the Health & Aging Brain Study -Health Disparities (HABS-HD) cohort. METHODS: PET amyloid (florbetaben) data was analyzed from 34 Mexican American and 22 non-Hispanic white participants. RESULTS: Glucagon (t = 3.84, p <  0.001) and insulin (t = -2.56, p = 0.02) were both significantly related to global SUVR levels among Mexican Americans. Glucagon and insulin were both related to most ROIs. No metabolic markers were significantly related to brain amyloid levels among non-Hispanic whites. CONCLUSION: Metabolic markers are related to brain amyloid burden among Mexican Americans. Given the increased risk for diabetes, additional research is needed to determine the impact of diabetes on core AD biomarkers among this underserved population.

Mild Cognitive Impairment, Reversion Rates, and Associated Factors: Comparison of Two Diagnostic Approaches. - Overton, Marieclaire; Sjögren, Benjamin; Elmståhl, Sölve; Rosso, Aldana (J Alzheimers Dis, 2022)
BACKGROUND: As mild cognitive impairment (MCI) is typically used to identify prodromal stages of dementia, it is essential to identify MCI criteria with high diagnostic stability and prediction of dementia. Moreover, further investigation into pinpointing key factors for reversion is required to foresee future prognosis of MCI patients accurately. OBJECTIVE: To explore disparities in diagnostic stability by examining reversion rates produced by two operationalizations of the MCI definition: the widely applied Petersen criteria and a version of the Neuropsychological (NP) criteria and to identify cognitive, lifestyle, and health related factors for reversion. METHODS: MCI was retrospectively classified in a sample from the Swedish community-based study Good Aging in Skåne with the Petersen criteria (n = 744, median follow-up = 7.0 years) and the NP criteria (n = 375, median follow-up, 6.7 years), respectively. Poisson regression models estimated the effect of various factors on the likelihood of incident reversion. RESULTS: Reversion rates were 323/744 (43.4%, 95% confidence intervals (CI): 39.8; 47.0) and 181/375 (48.3% 95% CI: 43.2; 53.5) for the Petersen criteria and NP criteria, respectively. Participants with impairment in a single cognitive domain, regular alcohol consumption, living with someone, older age, and lower body mass index had a higher likelihood of reverting to normal. CONCLUSION: Reversion rates were similar for Petersen and NP criteria indicating that one definition is not superior to the other regarding diagnostic stability. Additionally, the results highlight important aspects such as multiple domain MCI, cohabitation, and the role of alcohol on predicting the trajectory of those diagnosed with MCI.

Mild Traumatic Brain Injury is Related to Elevated Cerebrospinal Fluid Tau in Alzheimer's Disease Dementia. - LoBue, Christian; Kelley, Brendan J; Hart, John; Helphrey, Jessica; Schaffert, Jeff; Cullum, C Munro; Peters, Matthew E; Douglas, Peter M (J Alzheimers Dis, 2022)
Few studies have examined an association between mild traumatic brain injury (mTBI) and Alzheimer's disease (AD). For this reason, we compared an AD dementia group with an mTBI history (n = 10) to a matched AD control group (n = 20) on measures of cognitive function, cerebral glucose metabolism, and markers of amyloid and tau deposition. Only a trend and medium-to-large effect size for higher phosphorylated and total tau was identified for the mTBI group. A history of mTBI may be associated with greater tau in AD, indicating a potential pathway for increasing risk for AD, though further evaluation with larger samples is needed.

A Mitochondrial DNA Haplogroup Defines Patterns of Five-Year Cognitive Change. - Watts, Amber; Chalise, Prabhakar; Hu, Jinxiang; Hui, Dongwei; Pa, Judy; Andrews, Shea J; Michaelis, Elias K; Swerdlow, Russell H (J Alzheimers Dis, 2022)
BACKGROUND: Mitochondrial DNA (mtDNA) may play a role in Alzheimer's disease (AD) and cognitive decline. A particular haplogroup of mtDNA, haplogroup J, has been observed more commonly in patients with AD than in cognitively normal controls. OBJECTIVE: We used two mtDNA haplogroups, H and J, to predict change in cognitive performance over five years. We hypothesized that haplogroup J carriers would show less cognitive resilience. METHODS: We analyzed data from 140 cognitively normal older adults who participated in the University of Kansas Alzheimer's Disease Research Center clinical cohort between 2011 and 2020. We used factor analysis to create three composite scores (verbal memory, attention, and executive function) from 11 individual cognitive tests. We performed latent growth curve modeling to describe trajectories of cognitive performance and change adjusting for age, sex, years of education, and APOE ɛ4 allele carrier status. We compared haplogroup H, the most common group, to haplogroup J, the potential risk group. RESULTS: Haplogroup J carriers had significantly lower baseline performance and slower rates of improvement on tests of verbal memory compared to haplogroup H carriers. We did not observe differences in executive function or attention. CONCLUSION: Our results reinforce the role of mtDNA in changes to cognitive function in a domain associated with risk for dementia, verbal memory, but not with other cognitive domains. Future research should investigate the distinct mechanisms by which mtDNA might affect performance on verbal memory as compared to other cognitive domains across haplogroups.

Mitochondrial Targeting of Amyloid-β Protein Precursor Intracellular Domain Induces Hippocampal Cell Death via a Mechanism Distinct from Amyloid-β. - Sandberg, Alexandra A; Manning, Evan; Wilkins, Heather M; Mazzarino, Randall; Minckley, Taylor; Swerdlow, Russell H; Patterson, David; Qin, Yan; Linseman, Daniel A (J Alzheimers Dis, 2022)
BACKGROUND: Amyloid-β (Aβ) is a principal cleavage product of amyloid-β protein precursor (AβPP) and is widely recognized as a key pathogenic player in Alzheimer's disease (AD). Yet, there is increasing evidence of a neurotoxic role for the AβPP intracellular domain (AICD) which has been proposed to occur through its nuclear function. Intriguingly, there is a γ-secretase resident at the mitochondria which could produce AICD locally. OBJECTIVE: We examined the potential of AICD to induce neuronal apoptosis when targeted specifically to the mitochondria and compared its mechanism of neurotoxicity to that of Aβ. METHODS: We utilized transient transfection of HT22 neuronal cells with bicistronic plasmids coding for DsRed and either empty vector (Ires), Aβ, AICD59, or mitochondrial-targeted AICD (mitoAICD) in combination with various inhibitors of pathways involved in apoptosis. RESULTS: AICD induced significant neuronal apoptosis only when targeted to the mitochondria. Apoptosis required functional mitochondria as neither Aβ nor mitoAICD induced significant toxicity in cells devoid of mitochondrial DNA. Both glutathione and a Bax inhibitor protected HT22 cells from either peptide. However, inhibition of the mitochondrial permeability transition pore only protected from Aβ, while pan-caspase inhibitors uniquely rescued cells from mitoAICD. CONCLUSION: Our results show that AICD displays a novel neurotoxic function when targeted to mitochondria. Moreover, mitoAICD induces apoptosis via a mechanism that is distinct from that of Aβ. These findings suggest that AICD produced locally at mitochondria via organelle-specific γ-secretase could act in a synergistic manner with Aβ to cause mitochondrial dysfunction and neuronal death in AD.

Monitoring Alzheimer's Disease Progression in Mild Cognitive Impairment Stage Using Machine Learning-Based FDG-PET Classification Methods. - Beheshti, Iman; Geddert, Natasha; Perron, Jarrad; Gupta, Vinay; Albensi, Benedict C; Ko, Ji Hyun (J Alzheimers Dis, 2022)
BACKGROUND: We previously introduced a machine learning-based Alzheimer's Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects. OBJECTIVE: We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD. METHODS: MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior. RESULTS: The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7-0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p <  0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q <  0.01). CONCLUSION: These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD.

Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study. - Weinstein, Galit; O'Donnell, Adrienne; Davis-Plourde, Kendra; Zelber-Sagi, Shira; Ghosh, Saptaparni; DeCarli, Charles S; Thibault, Emma G; Sperling, Reisa A; Johnson, Keith A; Beiser, Alexa S; Seshadri, Sudha (J Alzheimers Dis, 2022)
BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 >  1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p <  0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p <  0.001; β= 1.59±0.38, p <  0.001, and β= 1.52±0.54, p = 0.008, respectively). CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

Noninvasive Antemortem Detection of Retinal Prions by a Fluorescent Tracer. - Aguilar-Calvo, Patricia; Sevillano, Alejandro M; Rasool, Suhail; Cao, Kevin J; Randolph, Lyndsay M; Rissman, Robert A; Sarraf, Stella T; Yang, Jerry; Sigurdson, Christina J (J Alzheimers Dis, 2022)
BACKGROUND: Neurodegenerative diseases are widespread yet challenging to diagnose and stage antemortem. As an extension of the central nervous system, the eye harbors retina ganglion cells vulnerable to degeneration, and visual symptoms are often an early manifestation of neurodegenerative disease. OBJECTIVE: Here we test whether prion protein aggregates could be detected in the eyes of live mice using an amyloid-binding fluorescent probe and high-resolution retinal microscopy. METHODS: We performed retinal imaging on an experimental mouse model of prion-associated cerebral amyloid angiopathy in a longitudinal study. An amyloid-binding fluorophore was intravenously administered, and retinal imaging was performed at timepoints corresponding to early, mid-, and terminal prion disease. Retinal amyloid deposits were quantified and compared to the amyloid load in the brain. RESULTS: We report that by mid-prion disease (50% timepoint), discrete fluorescent foci appeared adjacent to the optic disc. By later timepoints, the fluorescent foci partly surrounded the optic disc and tracked along retinal vasculature. CONCLUSION: The progression of perivascular amyloid can be directly monitored in the eye by live imaging, illustrating the utility of this technology for diagnosing and monitoring the progression of cerebral amyloid-angiopathy.

Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light. - Agger, Mikkel Pejstrup; Carstensen, Marcus Schultz; Henney, Mark Alexander; Hansen, Luna Skytte; Baandrup, Anders Ohlhues; Nguyen, Mai; Petersen, Paul Michael; Madsen, Kristoffer Hougaard; Kjær, Troels Wesenberg (J Alzheimers Dis, 2022)
BACKGROUND: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer's disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted. OBJECTIVE: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE). METHODS: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next. RESULTS: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14). CONCLUSION: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

A Novel Panel of Plasma Proteins Predicts Progression in Prodromal Alzheimer's Disease. - Araújo, Daniella Castro; Veloso, Adriano Alonso; Gomes, Karina Braga; de Souza, Leonardo Cruz; Ziviani, Nivio; Caramelli, Paulo (J Alzheimers Dis, 2022)
BACKGROUND: A cheap and minimum-invasive method for early identification of Alzheimer's disease (AD) pathogenesis is key to disease management and the success of emerging treatments targeting the prodromal phases of the disease. OBJECTIVE: To develop a machine learning-based blood panel to predict the progression from mild cognitive impairment (MCI) to dementia due to AD within a four-year time-to-conversion horizon. METHODS: We created over one billion models to predict the probability of conversion from MCI to dementia due to AD and chose the best-performing one. We used Alzheimer's Disease Neuroimaging Initiative (ADNI) data of 379 MCI individuals in the baseline visit, from which 176 converted to AD dementia. RESULTS: We developed a machine learning-based panel composed of 12 plasma proteins (ApoB, Calcitonin, C-peptide, CRP, IGFBP-2, Interleukin-3, Interleukin-8, PARC, Serotransferrin, THP, TLSP 1-309, and TN-C), and which yielded an AUC of 0.91, accuracy of 0.91, sensitivity of 0.84, and specificity of 0.98 for predicting the risk of MCI patients converting to dementia due to AD in a horizon of up to four years. CONCLUSION: The proposed machine learning model was able to accurately predict the risk of MCI patients converting to dementia due to AD in a horizon of up to four years, suggesting that this model could be used as a minimum-invasive tool for clinical decision support. Further studies are needed to better clarify the possible pathophysiological links with the reported proteins.

Obesity-Associated Neurodegeneration Pattern Mimics Alzheimer's Disease in an Observational Cohort Study. - Morys, Filip; Potvin, Olivier; Zeighami, Yashar; Vogel, Jacob; Lamontagne-Caron, Rémi; Duchesne, Simon; Dagher, Alain (J Alzheimers Dis, 2022)
BACKGROUND: Excess weight in adulthood leads to health complications such as diabetes, hypertension, or dyslipidemia. Recently, excess weight has also been related to brain atrophy and cognitive decline. Reports show that obesity is linked with Alzheimer's disease (AD)-related changes, such as cerebrovascular damage or amyloid-β accumulation. However, to date no research has conducted a direct comparison between brain atrophy patterns in AD and obesity. OBJECTIVE: Here, we compared patterns of brain atrophy and amyloid-β/tau protein accumulation in obesity and AD using a sample of over 1,300 individuals from four groups: AD patients, healthy controls, obese otherwise healthy individuals, and lean individuals. METHODS: We age- and sex-matched all groups to the AD-patients group and created cortical thickness maps of AD and obesity. This was done by comparing AD patients with healthy controls, and obese individuals with lean individuals. We then compared the AD and obesity maps using correlation analyses and permutation-based tests that account for spatial autocorrelation. Similarly, we compared obesity and AD brain maps with amyloid-β and tau protein maps from other studies. RESULTS: Obesity maps were highly correlated with AD maps but were not correlated with amyloid-β/tau protein maps. This effect was not accounted for by the presence of obesity in the AD group. CONCLUSION: Our research confirms that obesity-related grey matter atrophy resembles that of AD. Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD.

Olfactory Bulb Integrity in Frontotemporal Dementia and Alzheimer's Disease. - Carnemolla, Sarah; Kumfor, Fiona; Liang, Cheng Tao; Foxe, David; Ahmed, Rebekah; Piguet, Olivier (J Alzheimers Dis, 2022)
BACKGROUND: Olfactory dysfunction is highly prevalent in dementia syndromes, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). The structural integrity of the olfactory bulb (OB) is thought to play a critical role in odor detection and identification, but no MRI study has measured OB volume in FTD, or measured OB volume longitudinally in AD. OBJECTIVE: To measure OB volume in FTD and AD patients longitudinally using MRI. METHODS: This study measured OB volumes using MRI in patients diagnosed with behavioral-variant FTD (n = 55), semantic dementia (n = 34), progressive non-fluent aphasia (n = 30), AD (n = 50), and healthy age-matched controls (n = 55) at their first visit to a dementia research clinic ('baseline'). Imaging data in patients 12-months later were analyzed where available (n = 84) for longitudinal assessment. Volumes of subcortical and cortical olfactory regions ('olfactory network') were obtained via surface-based morphometry. RESULTS: Results revealed that in AD and FTD at baseline, OB volumes were similar to controls, whereas volumes of olfactory network regions were significantly reduced in all patient groups except in progressive non-fluent aphasia. Longitudinal data revealed that OB volume became significantly reduced (10-25% volume reduction) in all dementia groups with disease progression. CONCLUSION: Olfactory dysfunction is common in patients diagnosed with AD or FTD, but our results indicate that there is no detectable volume loss to the OBs upon first presentation to the clinic. Our findings indicate that the OBs become detectably atrophied later in the disease process. OB atrophy indicates the potential usefulness for OBs to be targeted in interventions to improve olfactory function.

Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer's Disease: Data from the Zabút Aging Project. - Panzarella, Vera; Mauceri, Rodolfo; Baschi, Roberta; Maniscalco, Laura; Campisi, Giuseppina; Monastero, Roberto (J Alzheimers Dis, 2022)
BACKGROUND: The relationship between Alzheimer's disease (AD) and periodontitis has been recently investigated with heterogenous results. OBJECTIVE: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabút Aging Project, a community-based cohort study performed in a rural community in Sicily, Italy. METHODS: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment [aMCI], and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related quality of life (OHR-QoL) were evaluated. RESULTS: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than aMCI (p = 0.009) and controls (p = 0.001). Furthermore, the "M" component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p < 0.001) and controls (p < 0.001). A Poisson regression model revealed that age (p < 0.001), male gender (p = 0.001), and AD (p = 0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p = 0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p = 0.004). OHR-QoL scores did not differ among the groups. CONCLUSION: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum. These data remain to be confirmed in larger population-based cohorts.
Keywords: Aging; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Cohort Studies; Humans; Male; Neuropsychological Tests; Oral Health; Quality of Life

The Outcome of Patients with Amyloid-Negative Amnestic Mild Cognitive Impairment. - Cardoso, Sandra; Silva, Dina; Alves, Luísa; Guerreiro, Manuela; Mendonça, Alexandre de (J Alzheimers Dis, 2022)
BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) are usually at an initial stage of Alzheimer's disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology characteristic of AD. The significance of amyloid-negative aMCI is not presently clear. OBJECTIVE: To know the etiology and prognosis of amyloid-negative aMCI. METHODS: Patients who fulfilled criteria for aMCI and were amyloid negative were selected from a large cohort of non-demented patients with cognitive complaints and were followed with clinical and neuropsychological assessments. RESULTS: Few amyloid-negative aMCI had evidence of neurodegeneration at the baseline, as reflected in cerebrospinal fluid elevated tau protein levels. About half of the patients remained essentially stable for long periods of time. Others manifested a psychiatric disorder that was not apparent at baseline, namely major depression or bipolar disorder. Remarkably, about a quarter of patients developed neurodegenerative disorders other than AD, mostly frontotemporal dementia or Lewy body disease. CONCLUSION: Amyloid-negative aMCI is a heterogeneous condition. Many patients remain clinically stable, but others may later manifest psychiatric conditions or evolve to neurodegenerative disorders. Prudence is needed when communicating to the patient and family the results of biomarkers, and clinical follow-up should be advised.

Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner. - Bittar, Alice; Al-Lahham, Rabab; Bhatt, Nemil; Moore, Kenya; Montalbano, Mauro; Jerez, Cynthia; Fung, Leiana; McAllen, Salome; Ellsworth, Anna; Kayed, Rakez (J Alzheimers Dis, 2022)
BACKGROUND: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies. OBJECTIVE: We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy. METHODS: Aged mice received a single intravenous injection of 120 μg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays. RESULTS: TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo. CONCLUSION: This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains.

Pelargonidin and Berry Intake Association with Alzheimer's Disease Neuropathology: A Community-Based Study. - Agarwal, Puja; Holland, Thomas M; James, Bryan D; Cherian, Laurel J; Aggarwal, Neelum T; Leurgans, Sue E; Bennett, David A; Schneider, Julie A (J Alzheimers Dis, 2022)
BACKGROUND: An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer's dementia risk. OBJECTIVE: This study investigated if pelargonidin or berry intake is associated with Alzheimer's disease (AD) neuropathology in human brains. METHODS: The study was conducted among 575 deceased participants (age at death = 91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed. RESULTS: In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) = -0.293 (0.14), p = 0.038), and fewer phosphorylated tau tangles (β (SE) = -0.310, p = 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) = -0.227 (0.11), p = 0.037) and pelargonidin (Q4 versus Q1: β (SE) = -0.401 (0.16), p = 0.011; p trend = 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p = 0.004) and pelargonidin (ptrend = 0.007) intake were associated with fewer phosphorylated tau tangles. CONCLUSION: Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.

Peptidylarginine Deiminase and Alzheimer's Disease. - Wang, Lai; Chen, Hongyang; Tang, Jing; Guo, Zhengwei; Wang, Yanming (J Alzheimers Dis, 2022)
Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer's disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD.
Keywords: Alzheimer Disease; Animals; Cerebral Cortex; Citrulline; Hippocampus; Humans; Isoenzymes; Protein Processing, Post-Translational; Protein-Arginine Deiminases

Perivascular Space Predicts Brain Hypometabolism of Individuals with Underlying Amyloid Pathology. - Shi, Xiaolei; Zhou, Nan; Sun, Bin; Wu, Yongshun; Hu, Yachun; Ning, Yuping (J Alzheimers Dis, 2022)
BACKGROUND: Reduced signal on fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valid proxy for neurodegeneration in Alzheimer's disease (AD). Perivascular space (PVS) is believed to be associated with AD pathology and cognitive decline. OBJECTIVE: This study aimed to investigate the associations of PVS with FDG-PET and cognitive performance based on the burden of amyloid pathology. METHODS: We used magnetic resonance imaging (MRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). MRI-visible PVS in basal ganglia (BG) and centrum semi-oval (CSO) were visually classified as: none/mild, moderate or frequent/severe. The association of PVS with brain FDG-PET was explored based on the burden of amyloid pathology, where a cerebrospinal fluid (CSF) t-tau/Aβ42 with the ratio≥0.27 was defined as high amyloid pathology. Moreover, the relationships between PVS and cognitive performance variables (ADNI-MEM and ADNI-EF) were studied. RESULTS: For participants with higher tau/Aβ42 ratio, CSO-PVS severity was independently associated with lower FDG-PET. There were significant interaction effects between moderate or frequent/severe CSO-PVS and time on FDG decline in people with high amyloid pathology. The interaction between CSO-PVS and time (follow-up) was consistently associated with ADNI-MEM and ADNI-EF decline in individuals with high amyloid pathology. CONCLUSION: The study established the differential utility of PVS in BG and CSO for predicting brain metabolism. These findings suggest that CSO-PVS serves as a contributing factor to brain metabolism and cognitive decline associated with amyloid pathology.

Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics. - Rippon, Brady; Palta, Priya; Tahmi, Mouna; Sherwood, Greysi; Soto, Luisa; Cespedes, Sandino; Mesen, Yanette; He, Hengda; Laing, Krystal; Moreno, Herman; Teresi, Jeanne; Razlighi, Qolamreza; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. OBJECTIVE: To relate plasma amyloid-β (Aβ), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aβ, measured using positron emission tomography (PET), examine the accuracy of plasma Aβ to predict brain Aβ positivity, and the relation of APOE ɛ4 with plasma Aβ. METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aβ 42/Aβ 40 ratio measured with Simoa. Brain Aβ burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. RESULTS: Plasma Aβ 42/Aβ 40 ratio was inversely associated with global Aβ SUVR (β= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aβ positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p <  0.0001) showed that the optimal threshold for plasma Aβ 42/Aβ 40 ratio in relation to brain Aβ positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8% . APOE ɛ4 carriers had lower Aβ 42/Aβ 40 ratio and a higher Aβ positivity determined with the Aβ 42/Aβ 40 ratio threshold of 0.060. CONCLUSION: Plasma Aβ 42/Aβ 40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

Plasma Cholesterol Levels as Potential Nutritional Biomarkers for Lewy Body Dementia. - Dou, Yuchao; Liu, Shuai; Li, Yuqing; Wu, Hao; Chen, Hui; Ji, Yong (J Alzheimers Dis, 2022)
BACKGROUND: The relationship between cholesterol level and the risk of developing Alzheimer's disease has been well established, but the relationship between cholesterol level and Lewy body dementia (LBD) is still not well known. OBJECTIVE: The aim of this case-control study was to explore the association between blood cholesterol levels and LBD in Chinese older adults. METHODS: A total of 65 patients with LBD and 110 older adult controls were enrolled during the study period. The levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting glucose were measured separately. The associations between LBD, blood cholesterol levels, and fasting glucose levels were assessed using multiple binary logistic regression analyses adjusted for multiple covariates. RESULTS: Increased plasma LDL-C levels and lower HDL-C levels were independently associated with the risk of LBD in models adjusted for age, sex, education, alcohol use status, smoking status, and vascular disorders. Higher fasting glucose levels may be associated with the risk of LBD. CONCLUSION: The results of this study suggest that elevated levels of LDL-C and reduced levels of HDL-C were associated with LBD development and therefore are potential nutritional risk factors for LBD. Adjusting diet and individualized and effective cholesterol-lowering therapy in high-risk adults may aid in the prevention or management of LBD.

Plasma Myeloperoxidase as a Potential Biomarker of Patient Response to Anti-Dementia Treatment in Alzheimer's Disease. - Wright, Joy R; Deen, Quazi Fahm E; Stevenson, Anna; Telford-Cooke, Leolie; Parker, Craig; Martin-Ruiz, Carmen; Steinert, Joern R; Kalaria, Raj N; Mukaetova-Ladinska, Elizabeta B (J Alzheimers Dis, 2022)
BACKGROUND: Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Anti-dementia treatment may facilitate efflux of Aβ and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment. OBJECTIVE: We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration. METHODS: Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA. RESULTS: AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p >  0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r = 0.5080; p = 0.011) and carer distress (r = 0.5022; p = 0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p <  0.001), which decreased at 6 months (p <  0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p = 0.028), and for AD patients with deterioration in Cornell assessment score (p = 0.044). CONCLUSION: Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker.

Polygenic Scores of Alzheimer's Disease Risk Genes Add Only Modestly to APOE in Explaining Variation in Amyloid PET Burden. - Ramanan, Vijay K; Heckman, Michael G; Przybelski, Scott A; Lesnick, Timothy G; Lowe, Val J; Graff-Radford, Jonathan; Mielke, M; Jack, Clifford R; Knopman, David S; Petersen, Ronald C; Ross, Owen A; Vemuri, Prashanthi (J Alzheimers Dis, 2022)
BACKGROUND: Brain accumulation of amyloid-β is a hallmark event in Alzheimer's disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia. OBJECTIVE: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population. METHODS: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained. RESULTS: Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p = 1.51×10-50) and ADNI (p = 3.21×10-64). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels. CONCLUSION: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.

Post-Stroke Cognitive Impairment: Epidemiology, Risk Factors, and Management. - Huang, Yu-Yuan; Chen, Shi-Dong; Leng, Xin-Yi; Kuo, Kevin; Wang, Zuo-Teng; Cui, Mei; Tan, Lan; Wang, Kai; Dong, Qiang; Yu, Jin-Tai (J Alzheimers Dis, 2022)
Stroke, characterized as a neurological deficit of cerebrovascular cause, is very common in older adults. Increasing evidence suggests stroke contributes to the risk and severity of cognitive impairment. People with cognitive impairment following stroke often face with quality-of-life issues and require ongoing support, which have a profound effect on caregivers and society. The high morbidity of post-stroke cognitive impairment (PSCI) demands effective management strategies, in which preventive strategies are more appealing, especially those targeting towards modifiable risk factors. In this review article, we attempt to summarize existing evidence and knowledge gaps on PSCI: elaborating on the heterogeneity in current definitions, reporting the inconsistent findings in PSCI prevalence in the literature, exploring established or less established predictors, outlining prevention and treatment strategies potentially effective or currently being tested, and proposing promising directions for future research.
Keywords: Aged; Cognitive Dysfunction; Humans; Prevalence; Risk Factors; Stroke

Potential Involvement of Varicella Zoster Virus in Alzheimer's Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1. - Cairns, Dana M; Itzhaki, Ruth F; Kaplan, David L (J Alzheimers Dis, 2022)
BACKGROUND: Varicella zoster virus (VZV) has been implicated in Alzheimer's disease (AD), and vaccination against shingles, caused by VZV, has been found to decrease the risk of AD/dementia. VZV might reside latently in brain, and on reactivation might cause direct damage leading to AD, as proposed for herpes simplex virus type 1 (HSV-1), a virus strongly implicated in AD. Alternatively, shingles could induce neuroinflammation and thence, reactivation of HSV-1 in brain. OBJECTIVE: To investigate these possibilities by comparing the effects of VZV and HSV-1 infection of cultured cells, and the action of VZV infection on cells quiescently infected with HSV-1. METHODS: We infected human-induced neural stem cell (hiNSC) cultures with HSV-1 and/or VZV and sought the presence of AD-related phenotypes such as amyloid-β (Aβ) and P-tau accumulation, gliosis, and neuroinflammation. RESULTS: Cells infected with VZV did not show the main AD characteristics, Aβ and P-tau accumulation, which HSV-1 does cause, but did show gliosis and increased levels of pro-inflammatory cytokines, suggesting that VZV's action relating to AD/dementia is indirect. Strikingly, we found that VZV infection of cells quiescently infected with HSV-1 causes reactivation of HSV-1 and consequent AD-like changes, including Aβ and P-tau accumulation. CONCLUSION: Our results are consistent with the suggestion that shingles causes reactivation of HSV1 in brain and with the protective effects against AD of various vaccines, as well as the decrease in herpes labialis reported after certain types of vaccination. They support an indirect role for VZV in AD/dementia via reactivation of HSV-1 in brain.

Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer's Disease Neuropathology. - Kok, Frédérique K; van Leerdam, Suzanne L; de Lange, Elizabeth C M (J Alzheimers Dis, 2022)
Alzheimer's disease (AD) is the most common form of dementia and typically characterized by the accumulation of amyloid-β plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact. Studies presented in this review show that NDAN subjects are generally higher educated and have a larger cognitive reserve. Furthermore, enhanced neural hypertrophy could compensate for hippocampal and cingulate neural atrophy in NDAN individuals. On a cellular level, these individuals show increased levels of neural stem cells and 'von Economo neurons'. Furthermore, in NDAN brains, binding of Aβ oligomers to synapses is prevented, resulting in decreased glial activation and reduced neuroinflammation. Overall, the evidence stated here strengthens the idea that some individuals are more resistant to AD pathology, or at least show an elongation of the asymptomatic state of the disease compared to others. Insights into the mechanisms underlying this resistance could provide new insight in understanding normal aging and AD itself. Further research should focus on factors and mechanisms that govern the NDAN cognitive resilience in order to find clues on novel biomarkers, targets, and better treatments of AD.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Hippocampus; Humans; Plaque, Amyloid; Synapses

Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project. - Toups, Kat; Hathaway, Ann; Gordon, Deborah; Chung, Henrianna; Raji, Cyrus; Boyd, Alan; Hill, Benjamin D; Hausman-Cohen, Sharon; Attarha, Mouna; Chwa, Won Jong; Jarrett, Michael; Bredesen, Dale E (J Alzheimers Dis, 2022)
BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Pre-Diagnostic Symptoms of Young-Onset Dementia in the General Practice up to Five Years Before Diagnosis. - Hendriks, Stevie; Peetoom, Kirsten; Tange, Huibert; van Bokhoven, Marloes A; van der Flier, Wiesje M; Bakker, Christian; Papma, Janne M; Koopmans, Raymond; Verhey, Frans; Köhler, Sebastian; de Vugt, Marjolein (J Alzheimers Dis, 2022)
BACKGROUND: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD. OBJECTIVE: Identify early symptoms that are more common in the pre-diagnostic phase of YOD. METHODS: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom's time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported. RESULTS: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77% ), for the highest percentage of correctly diagnosed persons. CONCLUSION: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD.

Prevalence of Depressive Symptoms in a Memory Clinic Cohort: A Retrospective Study. - Loreto, Flavia; Fitzgerald, Anna; Golemme, Mara; Gunning, Stephen; Win, Zarni; Patel, Neva; Carswell, Christopher; Perry, Richard; Kennedy, Angus; Edison, Paul; Malhotra, Paresh (J Alzheimers Dis, 2022)
BACKGROUND: Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer's disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. OBJECTIVE: To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging. METHODS: We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. RESULTS: One hundred forty-two (47%) patients had a history of significant depressive symptoms ('D+'). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients. CONCLUSION: Approximately half of patients who meet appropriate use criteria for amyloid PET had a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.

Prions and Neurodegenerative Diseases: A Focus on Alzheimer's Disease. - Crestini, Alessio; Santilli, Francesca; Martellucci, Stefano; Carbone, Elena; Sorice, Maurizio; Piscopo, Paola; Mattei, Vincenzo (J Alzheimers Dis, 2022)
Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer's disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.
Keywords: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Neurofibrillary Tangles; Neurons; Prion Proteins; Protein Aggregation, Pathological; Randomized Controlled Trials as Topic; Receptor, Metabotropic Glutamate 5; tau Proteins

Probiotic Bifidobacterium breve Prevents Memory Impairment Through the Reduction of Both Amyloid-β Production and Microglia Activation in APP Knock-In Mouse. - Abdelhamid, Mona; Zhou, Chunyu; Ohno, Kazuya; Kuhara, Tetsuya; Taslima, Ferdous; Abdullah, Mohammad; Jung, Cha-Gyun; Michikawa, Makoto (J Alzheimers Dis, 2022)
BACKGROUND: Probiotic supplementation reestablishes microbiome diversity and improves brain function in Alzheimer's disease (AD); their molecular mechanisms, however, have not yet been fully illustrated. OBJECTIVE: We investigated the effects of orally supplemented Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in AppNL-G-F mice. METHODS: Three-month-old AppNL-G-F mice were orally supplemented with B. breve MCC1274 for four months. The short-term memory function was evaluated using a novel object recognition test. Amyloid plaques, amyloid-β (Aβ) levels, Aβ fibril, amyloid-β protein precursor and its processing enzymes, its metabolic products, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated by immunohistochemistry, Aβ ELISA, western blotting, and immunofluorescence staining. The mRNA expression levels of pro- and anti-inflammatory cytokines were determined by qRT-PCR analysis. RESULTS: We found that the oral B. breve MCC1 274 supplementation prevented memory impairment in AppNL-G-F mice and decreased hippocampal Aβ levels through the enhancement of the a-disintegrin and metalloproteinase 10 (ADAM10) level. Moreover, administration of the probiotic activated the ERK/HIF-1α signaling pathway responsible for increasing the ADAM10 level and also attenuated microglial activation, which in turn led to reduction in the mRNA expression levels of pro-inflammatory cytokines in the brain. In addition, B. breve MCC1274 supplementation increased the level of synaptic proteins in the hippocampus. CONCLUSION: Our findings support the possibility that oral B. breve MCC1274 supplementation might be used as a potential preventive therapy for AD progression.
Keywords: Amyloid beta-Peptides; Animals; Bifidobacterium breve; Brain; Disease Models, Animal; Hippocampus; Memory Disorders; Mice; Mice, Transgenic; Microglia; Probiotics

Progression from Subjective Cognitive Decline to Mild Cognitive Impairment or Dementia: The Role of Baseline Cognitive Performance. - Jester, Dylan J; Vyhnálek, Martin; Andel, Ross; Marková, Hana; Nikolai, Tomas; Laczó, Jan; Matuskova, Veronika; Cechova, Katerina; Sheardova, Katerina; Hort, Jakub (J Alzheimers Dis, 2022)
BACKGROUND: Older adults with subjective cognitive decline (SCD) are at an increased risk of progression to mild cognitive impairment (MCI) or dementia. However, few have examined the specific cognitive tests that are associated with progression. OBJECTIVE: This study examined performance on 18 neuropsychological tests among participants with SCD who later progressed to MCI or dementia. METHODS: We included 131 participants from the Czech Brain Aging Study that had SCD at baseline. They completed a comprehensive neuropsychological battery including cognitive tests from the Uniform Data Set 2.0 enriched by the verbal memory test Rey Auditory Verbal Learning Test (RAVLT) and Rey-Osterrieth Complex Figure Test (ROCFT). RESULTS: Fifty-five participants progressed: 53% to non-amnestic MCI (naMCI), 44% to amnestic MCI (aMCI), and 4% to dementia. Scoring one SD below the mean at baseline on the RAVLT 1 and RAVLT 1-5 was associated with 133% (RAVLT 1; HR: 2.33 [1.50, 3.62]) and 122% (RAVLT 1-5; HR: 2.22 [1.55, 3.16]) greater risk of progression to MCI or dementia over 3.84 years on average. Worse performance on the RAVLT 5, RAVLT 1-5, RAVLT 30, and ROCFT-Recall was associated with progression to aMCI whereas worse performance on the RAVLT 1, TMT B, and Boston Naming Test was associated with progression to naMCI. CONCLUSION: At baseline, lower verbal memory performance was most strongly associated with progression to aMCI whereas lower executive or language performance was most strongly associated with progression to naMCI.

Proteomic Profiles of Neurodegeneration Among Mexican Americans and Non-Hispanic Whites in the HABS-HD Study. - O'Bryant, Sid E; Zhang, Fan; Petersen, Melissa; Hall, James R; Johnson, Leigh A; Yaffe, Kristine; Braskie, Meredith; Vig, Rocky; Toga, Arthur W; Rissman, Robert A (J Alzheimers Dis, 2022)
BACKGROUND: Hispanics are expected to experience the largest increase in Alzheimer's disease (AD) and AD related dementias over the next several decades. However, few studies have examined biomarkers of AD among Mexican Americans, the largest segment of the U.S. Hispanic population. OBJECTIVE: We sought to examine proteomic profiles of an MRI-based marker of neurodegeneration from the AT(N) framework among a multi-ethnic, community-dwelling cohort. METHODS: Community-dwelling Mexican Americans and non-Hispanic white adults and elders were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T MRI of the brain. A neurodegeneration MRI meta-ROI biomarker for the AT(N) framework was calculated. RESULTS: Data was examined from n = 1,291 participants. Proteomic profiles were highly accurate for detecting neurodegeneration (i.e., N+) among both Mexican Americans (AUC = 1.0) and non-Hispanic whites (AUC = 0.98). The proteomic profile of N + was different between ethnic groups. Further analyses revealed that the proteomic profiles of N + varied by diagnostic status (control, MCI, dementia) and ethnicity (Mexican American versus non-Hispanic whites) though diagnostic accuracy was high for all classifications. CONCLUSION: A proteomic profile of neurodegeneration has tremendous value and point towards novel diagnostic and intervention opportunities. The current findings demonstrate that the underlying biological factors associated with neurodegeneration are different between Mexican Americans versus non-Hispanic whites as well as at different levels of disease progression.

Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions. - Agüera-Ortiz, Luis; Babulal, Ganesh M; Bruneau, Marie-Andrée; Creese, Byron; D'Antonio, Fabrizia; Fischer, Corinne E; Gatchel, Jennifer R; Ismail, Zahinoor; Kumar, Sanjeev; McGeown, William J; Mortby, Moyra E; Nuñez, Nicolas A; et al. (J Alzheimers Dis, 2022)
Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.
Keywords: Caregivers; Dementia; Hallucinations; Humans; Psychotic Disorders; Schizophrenia

Race Differences in the Association Between Sleep Medication Use and Risk of Dementia. - Leng, Yue; Stone, Katie L; Yaffe, Kristine (J Alzheimers Dis, 2022)
BACKGROUND: The effect of sleep medications on cognition in older adults is controversial, possibly dependent upon sleep quality, and may differ by race. OBJECTIVE: To determine the longitudinal association between sleep medication use and incident dementia over 15 years, and to explore whether the association is independent of nighttime sleep disturbances and if it differs by race. METHODS: We examined 3,068 community-dwelling older adults (aged 74.1±2.9 years, 41.7% Black, 51.5% female) without dementia. Sleep medication use was recorded three times by asking "Do you take sleeping pills or other medications to help you sleep?" with the response options: "Never (0)", "Rarely (≤1/month)", "Sometimes (2-4/month)", "Often (5-15/month)", or "Almost Always (16-30/month)". Incident dementia was defined using hospitalization records, dementia medication prescription or clinically significant decline in global cognition. RESULTS: 138 (7.71%) of Whites and 34 (2.66%) of Blacks reported taking sleep medications "often or almost always". Whites were almost twice as likely to take all prescription hypnotics. 617 participants developed dementia over the follow-up. After adjustment for all covariates, participants who reported taking sleep medications ≥ 5/month versus ≤1/month were significantly more likely to develop dementia, and the association was only observed among Whites (HR = 1.79,1.21-2.66) but not Blacks (HR = 0.84,0.38-1.83); p for interaction = 0.048. Further adjustment for nighttime sleep did not appreciably alter the results. The association was similar for the cumulative frequency of sleep medication use and remained after introducing a time lag of 3 years. CONCLUSION: Frequent sleep medication use was associated with an increased risk of dementia in White older adults. Further research is needed to determine underlying mechanisms.

The Relationship Between Prior Cancer Diagnosis and All-Cause Dementia Progression Among US Adults. - Fowler, Mackenzie E; Wright, Nicole C; Triebel, Kristen; Rocque, Gabrielle B; Irvin, Ryan; Kennedy, Richard E (J Alzheimers Dis, 2022)
BACKGROUND: Cancer-related cognitive impairment (CRCI), a frequent effect of cancer and its treatments, shares common cognitive symptoms with dementia syndromes. Cross-sectional studies demonstrate an inverse relationship between cancer and dementia. However, the longitudinal relationship between dementia decline and cancer has not been investigated. OBJECTIVE: To evaluate the association between cancer and longitudinal progression of dementia. METHODS: We extracted electronic health record data from July 2003 to February 2020 from a single academic medical center. We identified dementia and cancer history prior to dementia using ICD-9/10 codes. We measured cognitive decline with the Alabama Brief Cognitive Screener (ABCs). We used adjusted linear mixed models to estimate baseline cognition and rate of progression by cancer history, including differences by race. RESULTS: The study included 3,809 participants with dementia, of which 672 (17.6%) had cancer history. Those with cancer history had higher baseline cognition (β: 0.62, 95% CI: -0.02-1.25), but similar rate of decline. Non-Hispanic Blacks had lower cognitive scores at baseline and throughout follow-up regardless of cancer status compared to non-Hispanic Whites and other races/ethnicities with and without cancer history. CONCLUSION: In this longitudinal retrospective study, participants with cancer history demonstrate better cognition at dementia diagnosis and no difference in cognitive decline than those without cancer history. Smoking and comorbidities attenuate this association and results indicate non-Hispanic Blacks have worse cognitive outcomes in dementia regardless of cancer history than other race/ethnicity groups. Further exploration of the role of smoking, comorbidities, and race/ethnicity on cancer and dementia-related cognitive decline is needed.

Relationship Between the Gut Microbiota and Alzheimer's Disease: A Systematic Review. - González Cordero, Elisa Marina; Cuevas-Budhart, Miguel Angel; Pérez Morán, Diana; Trejo Villeda, Miguel Angel; Gomez-Del-Pulgar Gª-Madrid, Mercedes (J Alzheimers Dis, 2022)
BACKGROUND: In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated. OBJECTIVE: To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer's disease. METHOD: Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish. RESULTS: Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review. CONCLUSION: The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic.
Keywords: Alzheimer Disease; Brain; Brain-Gut Axis; Cognitive Dysfunction; Gastrointestinal Microbiome; Humans

Relationship Between Weight-Change Patterns and Cognitive Function: A Retrospective Study. - Gong, Hong-Jian; Tang, Xingyao; Chai, Yin-He; Qiao, Yu-Shun; Xu, Hui; Patel, Ikramulhaq; Zhang, Jin-Yan; Simó, Rafael; Zhou, Jian-Bo (J Alzheimers Dis, 2022)
BACKGROUND: Obesity has been linked to cognitive impairment. However, how changes in body mass index (BMI) over the life course influence cognitive function remains unclear. OBJECTIVE: The influence of distinct weight-change patterns from young adulthood to midlife and late adulthood on cognitive function in older adults was explored. METHODS: A total of 5,809 individuals aged≥60 years were included and categorized into four groups on the basis of BMI change patterns. Cognitive function was assessed using four cognition tests in the baseline survey. The relationship between the weight-change patterns and cognition was evaluated using regression models. RESULTS: In comparison with participants who remained at non-obese, those moving from the non-obese to obese weight-change pattern from young (25 years of age) to middle adulthood showed lower Digit Symbol Substitution Test (DSST) scores (β= -1.28; 95% confidence interval [CI]: -2.24 to -0.32). A non-obese to obese change pattern from age 25 years of age to 10 years before baseline was associated with a higher risk of DSST impairment (odds ratio = 1.40; 95% CI: 1.09 to 1.79). In comparison with participants whose heaviest weight was recorded after 60 years of age, those with the heaviest weight between 18 and 40 years of age had lower DSST scores (β= -1.46; 95% CI: -2.77 to -1.52). CONCLUSION: Our results suggest that the transition from the non-obese to obese category in early adulthood and appearance of the heaviest weight between 18 and 40 years of age are associated with lower cognitive function in later life.

Relationships Between the Deposition of Amyloid-β and Tau Protein and Glymphatic System Activity in Alzheimer's Disease: Diffusion Tensor Image Study. - Ota, Miho; Sato, Noriko; Nakaya, Moto; Shigemoto, Yoko; Kimura, Yukio; Chiba, Emiko; Yokoi, Yuma; Tsukamoto, Tadashi; Matsuda, Hiroshi (J Alzheimers Dis, 2022)
BACKGROUND: Amyloid-β (Aβ) and tau protein accumulation in the brain is thought to be one of the causes of Alzheimer's disease (AD). Recent study found that the glymphatic system was waste drainage system in the brain and promoting the elimination of Aβ and tau protein. OBJECTIVE: Objective: We evaluated the relationships between the glymphatic system activity and Aβ and tau protein deposition. METHODS: Subjects were 21 patients with AD and 36 healthy subjects who underwent diffusion tensor imaging (DTI) scan and the positron emission tomography using with the Aβ tracer: 11C-PiB and the tau/inflammatory tracer: 18F-THK5351. We computed diffusion tensor image analysis along the perivascular space (DTI-ALPS) index as the proxy of glymphatic system activity and estimated the relationships between the DTI-ALPS index and Aβ and tau protein/inflammatory deposition. RESULTS: We found significant negative correlations between DTI-ALPS index and the standard uptake value ratio (SUVR) of 11C-PiB in the bilateral temporal and left parietal cortices and left posterior cingulate gyrus in all subjects. Further, we detected significant negative correlations between DTI-ALPS index and the SUVR of 18F-THK5351 in the bilateral temporal cortices and right parietal cortex in all participants, too. CONCLUSION: Our data suggested that DTI-ALPS index was a good biomarker for the evaluation of Aβ and tau deposition and neuroinflammation, and this marker might be effective to estimate the glymphatic system activity.

Rheumatoid Arthritis, Cognitive Impairment, and Neuroimaging Biomarkers: Results from the Mayo Clinic Study of Aging. - Vassilaki, Maria; Crowson, Cynthia S; Davis Iii, John M; Duong, Stephanie Q; Jones, David T; Nguyen, Aivi; Mielke, Michelle M; Vemuri, Prashanthi; Myasoedova, Elena (J Alzheimers Dis, 2022)
BACKGROUND: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population. OBJECTIVE: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer's disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA). METHODS: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years). RESULTS: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n = 33) and without RA (n = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p = 0.02). CONCLUSION: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA.
Keywords: Aged; Aging; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Arthritis, Rheumatoid; Biomarkers; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Positron-Emission Tomography

Risk of Alzheimer's Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. - Bukhbinder, Avram S; Ling, Yaobin; Hasan, Omar; Jiang, Xiaoqian; Kim, Yejin; Phelps, Kamal N; Schmandt, Rosemarie E; Amran, Albert; Coburn, Ryan; Ramesh, Srivathsan; Xiao, Qian; Schulz, Paul E (J Alzheimers Dis, 2022)
BACKGROUND: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized. OBJECTIVE: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database. METHODS: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up. RESULTS: From the unmatched sample of eligible patients (n = 2,356,479), PSM produced a sample of 935,887 flu-vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29-48) months; 5.1% (n = 47,889) of the flu-vaccinated patients and 8.5% (n = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59-0.61) and ARR was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4. CONCLUSION: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older.
Keywords: Adult; Aged; Alzheimer Disease; Chronic Disease; Cohort Studies; Female; Humans; Influenza, Human; Male; Middle Aged; Propensity Score; Vaccination

Risk of Dementia in Cancer Survivors: A Meta-Analysis of Population-Based Cohort Studies. - Zhang, Dan-Dan; Ou, Ya-Nan; Fu, Yan; Wang, Zhi-Bo; Huang, Liang-Yu; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2022)
BACKGROUND: A negative association between cancer and Alzheimer's disease (AD) was revealed. OBJECTIVE: We aimed to further explore the dementia risk among cancer survivors and then among cancer survivors who received cancer treatment in subsequent subgroup analyses. METHODS: Databases of PubMed, Embase, and Cochrane Library were systematically searched from inception to April 1, 2021, following PRISMA and MOOSE guidelines. Relative risks (RR) of dementia were pooled by a random-effects model stratifying the data by potential confounding factors to explore the heterogeneity. This study is registered with PROSPERO, number CRD42021250654. RESULTS: A total of 36 studies were included in this meta-analysis, of which 16 studies were about the risk of dementia in cancer survivors, and 20 studies were about the risk of dementia in survivors who accepted cancer treatment. The pooled RR reached 0.89 ([95% CI = 0.82-0.97], I2 = 97.9%) for dementia and 0.89 ([0.83-0.95], I2 = 92.6%) for AD in cancer survivors compared with non-cancer controls. Notably, both dementia risk and AD risk significantly decreased in survivors of colon, leukemia, small intestine, and thyroid cancers (RR ranged from 0.64 to 0.92). Furthermore, prostate cancer patients treated with androgen deprivation therapy exhibited a significantly increased risk of dementia (RR:1.18 [1.09-1.27], I2 = 89.5%) and AD (RR:1.17 [1.08-1.25], I2 = 81.3%), with evidence of between-study heterogeneity. CONCLUSION: Currently, available evidence suggests that the risk of dementia among cancer survivors is decreased. However, large-scale prospective cohort studies are warranted to further prove the association.

The Role of Amyloid, Tau, and APOE Genotype on the Relationship Between Informant-Reported Sleep Disturbance and Alzheimer's Disease Risks. - Kim, Hyun; Levine, Alina; Cohen, Daniel; Gehrman, Philip; Zhu, Xi; Devanand, Davangere P; Lee, Seonjoo; Goldberg, Terry E (J Alzheimers Dis, 2022)
BACKGROUND: The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD. OBJECTIVE: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline. METHODS: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models. RESULTS: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition. CONCLUSION: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD.

The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy. - Piccarducci, Rebecca; Caselli, Maria Chiara; Zappelli, Elisa; Ulivi, Leonardo; Daniele, Simona; Siciliano, Gabriele; Ceravolo, Roberto; Mancuso, Michelangelo; Baldacci, Filippo; Martini, Claudia (J Alzheimers Dis, 2022)
BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids. OBJECTIVE: The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ 1 - 40, Aβ 1 - 42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA. METHODS: For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC. RESULTS: The results highlighted a significant increase of Aβ 1 - 40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ 1 - 42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ 1 - 42/Aβ 1 - 40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies. CONCLUSION: In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.

Safety and Efficacy of Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Published and Unpublished Clinical Trials. - Lacorte, Eleonora; Ancidoni, Antonio; Zaccaria, Valerio; Remoli, Giulia; Tariciotti, Leonardo; Bellomo, Guido; Sciancalepore, Francesco; Corbo, Massimo; Lombardo, Flavia L; Bacigalupo, Ilaria; Canevelli, Marco; Piscopo, Paola; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Monoclonal antibodies (mAbs) are currently among the most investigated targets for potential disease-modifying therapies in Alzheimer's disease (AD). OBJECTIVE: Our objectives were to identify all registered trials investigating mAbs in MCI due to AD or AD at any stage, retrieve available published and unpublished data from all registered trials, and analyze data on safety and efficacy outcomes. METHODS: A systematic search of all registered trials on ClinicalTrials.gov and EUCT was performed. Available results were searched on both platforms and on PubMed, ISI Web of Knowledge, and The Cochrane Library. RESULTS: Overall, 101 studies were identified on 27 mAbs. Results were available for 50 trials investigating 12 mAbs. For 18 trials, data were available from both published and unpublished sources, for 21 trials only from published sources, and for 11 trials only from unpublished sources. Meta-analyses of amyloid-related imaging abnormalities (ARIA) events showed overall risk ratios of 10.65 for ARIA-E and of 1.75 for ARIA-H. The meta-analysis of PET-SUVR showed an overall significant effect of mAbs in reducing amyloid (SMD -0.88), but when considering clinical efficacy, data on CDR-SB showed that treated patients had a statistically significant but clinically non-relevant lower worsening (MD -0.15). CONCLUSION: Our results suggest that the risk-benefit profile of mAbs remains unclear. Research should focus on clarifying the effect of amyloid on cognitive decline, providing data on treatment response rate, and accounting for minimal clinically important difference. Research on mAbs should also investigate the possible long-term impact of ARIA events, including potential factors predicting their onset.
Keywords: Alzheimer Disease; Amyloid; Amyloidogenic Proteins; Amyloidosis; Antibodies, Monoclonal; Cognitive Dysfunction; Humans

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial. - Hua, Xue; Church, Kevin; Walker, William; L'Hostis, Philippe; Viardot, Geoffrey; Danjou, Philippe; Hendrix, Suzanne; Moebius, Hans J (J Alzheimers Dis, 2022)
BACKGROUND: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer's disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss. OBJECTIVE: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton. METHODS: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement. RESULTS: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo). CONCLUSION: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects.
Keywords: Aged; Alzheimer Disease; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Hepatocyte Growth Factor; Humans; Male

Salivary Proteomics Reveals Significant Changes in Relation to Alzheimer's Disease and Aging. - Contini, Cristina; Serrao, Simone; Manconi, Barbara; Olianas, Alessandra; Iavarone, Federica; Bizzarro, Alessandra; Masullo, Carlo; Castagnola, Massimo; Messana, Irene; Diaz, Giacomo; Cabras, Tiziana (J Alzheimers Dis, 2022)
BACKGROUND: Aging is a risk factor for several pathologies as Alzheimer's disease (AD). Great interest exists, therefore, in discovering diagnostic biomarkers and indicators discriminating biological aging and health status. To this aim, omic investigations of biological matrices, as saliva, whose sampling is easy and non-invasive, offer great potential. OBJECTIVE: Investigate the salivary proteome through a statistical comparison of the proteomic data by several approaches to highlight quali-/quantitative variations associated specifically either to aging or to AD occurrence, and, thus, able to classify the subjects. METHODS: Salivary proteomic data of healthy controls under-70 (adults) and over-70 (elderly) years old, and over-70 AD patients, obtained by liquid chromatography/mass spectrometry, were analyzed by multiple Mann-Whitney test, Kendall correlation, and Random-Forest (RF) analysis. RESULTS: Almost all the investigated proteins/peptides significantly decreased in relation to aging in elderly subjects, with or without AD, in comparison with adults. AD subjects exhibited the highest levels of α-defensins, thymosin β4, cystatin B, S100A8 and A9. Correlation tests also highlighted age/disease associated differences. RF analysis individuated quali-/quantitative variations in 20 components, as oxidized S100A8 and S100A9, α-defensin 3, P-B peptide, able to classify with great accuracy the subjects into the three groups. CONCLUSION: The findings demonstrated a strong change of the salivary protein profile in relation to the aging. Potential biomarkers candidates of AD were individuated in peptides/proteins involved in antimicrobial defense, innate immune system, inflammation, and in oxidative stress. RF analysis revealed the feasibility of the salivary proteome to discriminate groups of subjects based on age and health status.

Scavenging Reactive Oxygen Species Decreases Amyloid-β Levels via Activation of PI3K/Akt/GLUT1 Pathway in N2a/APP695swe Cells. - Peng, Yan; Zhang, Li; Zhou, Fanlin; Wang, Yangyang; Zhang, Xiong; Fan, Jianing; Li, Shijie; Li, Xiaoju; Li, Yu (J Alzheimers Dis, 2022)
BACKGROUND: Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer's disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear. OBJECTIVE: We aimed to explore the cause and mechanism of impaired glucose uptake in AD. METHODS: N2a/WT and N2a/APP695swe cells were cultured in vitro, and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again. RESULTS: GLUT1 expression was significantly decreased (p = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p >  0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p = 0.0006, p = 0.0008, p = 0.0009, p = 0.0001, p = 0.0013), while Aβ levels were significantly decreased (p = 0.0058, p = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p = 0.0008), and Aβ levels were increased (p = 0.0009, p = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p = 0.0002, p = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p = 0.0212, p = 0.0006). CONCLUSION: Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells.

Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function. - Kundu, Payel; Zimmerman, Benjamin; Quinn, Joseph F; Kaye, Jeffrey; Mattek, Nora; Westaway, Shawn K; Raber, Jacob (J Alzheimers Dis, 2022)
BACKGROUND: α-klotho might play a role in neurodegenerative diseases. OBJECTIVE: To determine levels of α-klotho and apoE in serum and cerebrospinal fluid (CSF) samples and their relationship with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). METHODS: All subjects were between age 39 to 83+ (n = 94). CDR and MMSE were administered to all participants. CSF was collected in the early afternoon by lumbar puncture. RESULTS: Serum and CSF levels of α-klotho are positively correlated and both predict scores on the MMSE and CDR, regardless of sex or apoE4 status. CONCLUSION: Our results demonstrate that α-klotho may be an important biomarker of cognitive health and neurodegeneration, and that relatively non-invasive sampling of α-klotho from serum is likely highly reflective of CSF levels.

Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model. - Sil, Annesha; Erfani, Arina; Lamb, Nicola; Copland, Rachel; Riedel, Gernot; Platt, Bettina (J Alzheimers Dis, 2022)
BACKGROUND: The prevalence of Alzheimer's disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. OBJECTIVE: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compare both sex- and genotype-dependent differences. METHODS: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting. RESULTS: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with subtle deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance. CONCLUSION: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Pathology, Molecular; Presenilin-1; Sex Characteristics

Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity. - Rahmani, Farzaneh; Wang, Qing; McKay, Nicole S; Keefe, Sarah; Hantler, Nancy; Hornbeck, Russ; Wang, Yong; Hassenstab, Jason; Schindler, Suzanne; Xiong, Chengjie; Morris, John C; Benzinger, Tammie L S; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Obesity is an increasingly recognized modifiable risk factor for Alzheimer's disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. OBJECTIVE: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. METHODS: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. RESULTS: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. CONCLUSION: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

Shortening of Saccades as a Possible Easy-to-Use Biomarker to Detect Risk of Alzheimer's Disease. - Hannonen, Sanna; Andberg, Sami; Kärkkäinen, Virve; Rusanen, Minna; Lehtola, Juha-Matti; Saari, Toni; Korhonen, Ville; Hokkanen, Laura; Hallikainen, Merja; Hänninen, Tuomo; Leinonen, Ville; Kaarniranta, Kai; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Wide-ranging functional defects in eye movements have been reported in Alzheimer's disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking. OBJECTIVE: To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD. METHODS: We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE = 28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE = 27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed. RESULTS: We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p < 0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p < 0.05). The KD error scores in the AD group differed significantly (p < 0.01) from the other groups. CONCLUSION: Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics.
Keywords: Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Humans; Neuropsychological Tests; Saccades

Single Nucleus Transcriptome Data from Alzheimer's Disease Mouse Models Yield New Insight into Pathophysiology. - Weller, Andrew E; Ferraro, Thomas N; Doyle, Glenn A; Reiner, Benjamin C; Crist, Richard C; Berrettini, Wade H (J Alzheimers Dis, 2022)
BACKGROUND: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer's disease (AD)-related pathology. OBJECTIVE: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice. METHODS: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA). RESULTS: We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr, Fth1, Pcsk1n, Malat1, Rpl37, Rtn1, Sepw1, Uba52, Mbp, Arl6ip5, Gm26917, Vwa1, and Pgrmc1. We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp, Rbm4b, Pnisr, Opcml, Cpne7, Adgrb1, Gabarapl2, Ubb, Ndfip1, Car11, and Stmn4. IPA identified 3 statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including 'FXR/RXR Activation', 'LXR/RXR Activation', and 'Acute Phase Response Signaling'. CONCLUSION: DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings.

Small RNA Sequencing in the Tg4-42 Mouse Model Suggests the Involvement of snoRNAs in the Etiology of Alzheimer's Disease. - Lio, Chit Tong; Kacprowski, Tim; Klaedtke, Maik; Jensen, Lars R; Bouter, Yvonne; Bayer, Thomas A; Kuss, Andreas W (J Alzheimers Dis, 2022)
BACKGROUND: The Tg4-42 mouse model for sporadic Alzheimer's disease (AD) has unique features, as the neuronal expression of wild type N-truncated Aβ4-42 induces an AD-typical neurological phenotype in the absence of plaques. It is one of the few models developing neuron death in the CA1 region of the hippocampus. As such, it could serve as a powerful tool for preclinical drug testing and identification of the underlying molecular pathways that drive the pathology of AD. OBJECTIVE: The aim of this study was to use a differential co-expression analysis approach for analyzing a small RNA sequencing dataset from a well-established murine model in order to identify potentially new players in the etiology of AD. METHODS: To investigate small nucleolar RNAs in the hippocampus of Tg4-42 mice, we used RNA-Seq data from this particular tissue and, instead of analyzing the data at single gene level, employed differential co-expression analysis, which takes the comparison to gene pair level and thus affords a new angle to the interpretation of these data. RESULTS: We identified two clusters of differentially correlated small RNAs, including Snord55, Snord57, Snord49a, Snord12, Snord38a, Snord99, Snord87, Mir1981, Mir106b, Mir30d, Mir598, and Mir99b. Interestingly, some of them have been reported to be functionally relevant in AD pathogenesis, as AD biomarkers, regulating tau phosphorylation, TGF-β receptor function or Aβ metabolism. CONCLUSION: The majority of snoRNAs for which our results suggest a potential role in the etiology of AD were so far not conspicuously implicated in the context of AD pathogenesis and could thus point towards interesting new avenues of research in this field.

The Spectrum of Alzheimer-Type Pathology in Cognitively Normal Individuals. - Walker, Jamie M; Dehkordi, Shiva Kazempour; Schaffert, Jeff; Goette, William; White Iii, Charles L; Richardson, Timothy E; Zare, Habil (J Alzheimers Dis, 2022)
BACKGROUND: The strongest risk factor for the development of Alzheimer's disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. OBJECTIVE: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. METHODS: Utilizing neuropathology data obtained from the National Alzheimer's Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual's Alzheimer-type pathology varies from the estimated normal range of pathology. RESULTS: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque score and Alzheimer's disease neuropathologic change remain at low levels. CONCLUSION: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-β (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be "resilient" against the pathology (significantly above the normative values for age, but still cognitively normal) or "resistant" to the development of pathology (significantly below the normative values for age).

Subjective Cognitive Decline: Is a Resilient Personality Protective Against Progression to Objective Cognitive Impairment? Findings from Two Community-Based Cohort Studies. - Aschwanden, Damaris; Sutin, Angelina R; Ledermann, Thomas; Luchetti, Martina; Stephan, Yannick; Sesker, Amanda A; Zhu, Xianghe; Terracciano, Antonio (J Alzheimers Dis, 2022)
BACKGROUND: Subjective cognitive decline (SCD) is related to personality functioning and risk of subsequent objective cognitive impairment. OBJECTIVE: The aim of this study was to examine whether lower neuroticism and higher conscientiousness-resilient personality traits-protect against conversion from SCD to objective cognitive impairment in two longitudinal community-based cohorts. METHODS: Data from the Health and Retirement Study (N = 1,741, Mean age = 68.64 years, Follow-up mean = 7.34 years) and the National Health and Aging Trends Survey (N = 258, Mean age = 79.34 years, Follow-up mean = 4.31 years) were analyzed using Cox regression analysis, controlling for sociodemographic covariates, symptoms of anxiety and depression, and apolipoprotein ɛ4. RESULTS: The pooled results showed that lower neuroticism and higher conscientiousness were associated with decreased risk of conversion from SCD to objective cognitive impairment. CONCLUSION: Among individuals with SCD, those with a resilient personality may have more cognitive and psychological reserve to maintain cognitive functioning and delay conversion to objective cognitive impairment. The findings further contribute to a better understanding of personality along the cognitive continuum: The observed effect sizes were smaller than those reported in cognitively normal individuals but larger than in individuals with mild cognitive impairment. Personality could provide useful information to identify individuals with SCD who may develop objective cognitive impairment-namely those who hold a vulnerable personality (higher neuroticism, lower conscientiousness).

Supplementation With Carotenoids, Omega-3 Fatty Acids, and Vitamin E Has a Positive Effect on the Symptoms and Progression of Alzheimer's Disease. - Nolan, John M; Power, Rebecca; Howard, Alan N; Bergin, Paula; Roche, Warren; Prado-Cabrero, Alfonso; Pope, George; Cooke, John; Power, Tommy; Mulcahy, Riona (J Alzheimers Dis, 2022)
BACKGROUND: Preliminary work by our center has reported behavior and functional benefits in patients with Alzheimer's disease (AD) following targeted micronutritional supplementation. OBJECTIVE: To build on the existing exploratory research and investigate the impact of these micronutrients on the natural progression of AD in a randomized controlled trial. METHODS: Patients with mild-moderate AD consumed daily 1 g fish oil (of which 500 mg DHA, 150 mg EPA), 22 mg carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, 2 mg zeaxanthin), and 15 mg vitamin E or placebo for 12 months in a double-blind, placebo-controlled, randomized clinical trial. Carotenoids, ω-3FAs, and vitamin E were quantified in blood. Carotenoids were also measured in skin. AD severity was measured using the mini-mental state examination and dementia severity rating scale tools. Behavior, mood, and memory were measured using an informant-based questionnaire. RESULTS: Following 12 months of supplementation, the active group (n = 50) compared to the placebo group (n = 27), demonstrated statistically significant improvements in skin carotenoid measurements, blood carotenoids, ω-3FAs, and vitamin E concentrations (p <  0.05, for all). The active group also performed better in objective measures of AD severity (i.e., memory and mood), with a statistically significant difference reported in the clinical collateral for memory (p <  0.001). CONCLUSION: Exponential increases in the prevalence of AD and its relentless progressive nature is driving the need for interventions that help to ameliorate symptoms and improve quality of life in AD patients. Given the positive outcomes demonstrated in this trial, this combined micronutrient dietary supplement should be considered in the overall management of AD.

Systemic Injection of Aged Blood Plasma in Adult C57BL/6 Mice Induces Neurophysiological Impairments in the Hippocampal CA1. - Huffels, Christiaan F M; van Dijk, Roland E; Karst, Henk; Meye, Frank J; Hol, Elly M; Middeldorp, Jinte (J Alzheimers Dis, 2022)
BACKGROUND: Aging is characterized by systemic alterations and forms an important risk factor for Alzheimer's disease. Recently, it has been indicated that blood-borne factors present in the systemic milieu contribute to the aging process. Exposing young mice to aged blood plasma results in impaired neurogenesis and synaptic plasticity in the dentate gyrus, as well as impaired cognition. Vice versa, treating aged mice with young blood plasma rescues impairments associated with aging. OBJECTIVE: Whether blood-borne factors are sufficient to drive impairments outside the dentate gyrus, how they impact neurophysiology, and how the functional outcome compares to impairments found in mouse models for AD is still unclear. METHODS: Here, we treated adult mice with blood plasma from aged mice and assessed neurophysiological parameters in the hippocampal CA1. RESULTS: Mice treated with aged blood plasma show significantly impaired levels of long-term potentiation (LTP), similar to those present in APP/PS1 mice. These impaired levels of LTP in plasma-treated mice are associated with alterations in basic properties of glutamatergic transmission and the enhanced activity of voltage-gated Ca2 + channels. CONCLUSION: Together, the data presented in this study show that blood-borne factors are sufficient to drive neurophysiological impairments in the hippocampal CA1.

A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease. - Lynn, Jessica; Park, Mingi; Ogunwale, Christiana; Acquaah-Mensah, George K (J Alzheimers Dis, 2022)
Dementias, including the type associated with Alzheimer's disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as "type 3 diabetes". In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.
Keywords: Alzheimer Disease; Animals; Biomarkers; Brain Chemistry; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Glucose; Glycation End Products, Advanced; Humans; Inflammation; Insulin Resistance; Oxidative Stress; Randomized Controlled Trials as Topic

Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice. - Eastman, Guillermo; Sharlow, Elizabeth R; Lazo, John S; Bloom, George S; Sotelo-Silveira, José R (J Alzheimers Dis, 2022)
BACKGROUND: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. OBJECTIVE: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). METHODS: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. RESULTS: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. CONCLUSION: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

Traumatic Brain Injury and Risk of Alzheimer's Disease and Related Dementias in the Population. - Mielke, Michelle M; Ransom, Jeanine E; Mandrekar, Jay; Turcano, Pierpaolo; Savica, Rodolfo; Brown, Allen W (J Alzheimers Dis, 2022)
BACKGROUND: Epidemiological studies examining associations between traumatic brain injury (TBI) and Alzheimer's disease and related dementias (ADRD) have yielded conflicting results, which may be due methodological differences. OBJECTIVE: To examine the relationship between the presence and severity of TBI and risk of ADRD using a population-based cohort with medical record abstraction for confirmation of TBI and ADRD. METHODS: All TBI events among Olmsted County, Minnesota residents aged >  40 years from 1985-1999 were confirmed by manual review and classified by severity. Each TBI case was randomly matched to two age-, sex-, and non-head injury population-based referents without TBI. For TBI events with non-head trauma, the Trauma Mortality Prediction Model was applied to assign an overall measure of non-head injury severity and corresponding referents were matched on this variable. Medical records were manually abstracted to confirm ADRD diagnosis. Cox proportional hazards models examined the relationship between TBI and severity with risk of ADRD. RESULTS: A total of 1,418 residents had a confirmed TBI (865 Possible, 450 Probable, and 103 Definite) and were matched to 2,836 referents. When combining all TBI severities, the risk of any ADRD was significantly higher for those with a confirmed TBI compared to referents (HR = 1.32, 95% CI: 1.11, 1.58). Stratifying by TBI severity, Probable (HR = 1.42, 95% CI: 1.05, 1.92) and Possible (HR = 1.29, 95% CI: 1.02-1.62) TBI was associated with an increased risk of ADRD, but not Definite TBI (HR = 1.22, 95% CI: 0.68, 2.18). CONCLUSION: Our analyses support including TBI as a potential risk factor for developing ADRD.

Undiagnosed Dementia Is Associated with Poor Physical Function in Older Adults. - McGrath, Ryan; Robinson-Lane, Sheria G; Klawitter, Lukus; Rhee, Yeong; Hamm, Jeremy M; McCourt, Mark E; Parker, Kelly; Hackney, Kyle J (J Alzheimers Dis, 2022)
BACKGROUND: Older adults with a cognitive impairment, including those not yet diagnosed, may have deficits in their physical function. OBJECTIVE: We sought to determine the associations of cognitive impairment consistent with dementia (CICD) diagnosis status on handgrip strength, gait speed, and functional disability in older adults. METHODS: The analytical sample included 8,383 adults aged ≥65-years without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. A handgrip dynamometer measured handgrip strength. Men with handgrip strength RESULTS: Persons with undiagnosed CICD had 1.37 (95% confidence interval (CI): 1.04-1.80) greater odds for weakness and 2.02 (CI: 1.39-2.94) greater odds for slow gait speed. Older adults with diagnosed CICD had 2.29 (CI: 1.32-3.97) greater odds for slowness and 1.85 (CI: 1.19-2.90) greater odds for functional disability. CONCLUSION: Screening for CICD could be recommended when defects in physical function are observed in older adults.

Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease. - Krishnadas, Natasha; Huang, Kun; Schultz, Stephanie A; Doré, Vincent; Bourgeat, Pierrick; Goh, Anita M Y; Lamb, Fiona; Bozinovski, Svetlana; Burnham, Samantha C; Robertson, Joanne S; Laws, Simon M; Maruff, Paul; et al. (J Alzheimers Dis, 2022)
BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. METHODS: Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.

Weight Loss and Alzheimer's Disease in Down Syndrome. - Fleming, Victoria; Helsel, Brian C; Ptomey, Lauren T; Rosas, H Diana; Handen, Benjamin; Laymon, Charles; Christian, Bradley T; Head, Elizabeth; Mapstone, Mark; Lai, Florence; Krinsky-McHale, Sharon; Zaman, Shahid; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. OBJECTIVE: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (-versus+) and/or decline in memory and mental status were associated with weight loss prior to AD progression. METHODS: Analyses included 261 adults with DS. PET data were acquired using [11C] PiB for Aβ and [18F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16-20 months was assessed in a subset of participants (n = 77). RESULTS: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16-20 months. CONCLUSION: Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS.

Yoga Prevents Gray Matter Atrophy in Women at Risk for Alzheimer's Disease: A Randomized Controlled Trial. - Krause-Sorio, Beatrix; Siddarth, Prabha; Kilpatrick, Lisa; Milillo, Michaela M; Aguilar-Faustino, Yesenia; Ercoli, Linda; Narr, Katherine L; Khalsa, Dharma S; Lavretsky, Helen (J Alzheimers Dis, 2022)
BACKGROUND: Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer's disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment. OBJECTIVE: In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET). METHODS: Eleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and Kirtan Kriya (KY + KK) while eleven women (mean age = 64.55, SD = 6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha = 0.05. Region-of-interest analysis was performed for hippocampus and amygdala. RESULTS: Compared to KY + KK, MET showed reductions in GMV in left prefrontal, pre- and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections. CONCLUSION: Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.

α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer's Disease. - Metsla, Kristel; Kirss, Sigrid; Laks, Katrina; Sildnik, Gertrud; Palgi, Mari; Palumaa, Teele; Tõugu, Vello; Palumaa, Peep (J Alzheimers Dis, 2022)
BACKGROUND: Alzheimer's disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-β (Aβ) peptides. Besides major amyloid-targeting approach there is the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess of extracellular copper. OBJECTIVE: In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and search for new copper-regulating ligands. METHODS: We used cell culture, ICP MS, and Drosophila melanogaster models of AD. RESULTS: We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in an SH-SY5Y-based neuronal cell model and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster models of AD from developing AD phenotype by improving locomotor activity of fruit fly with overexpression of human Aβ with Iowa mutation in the fly brain. In addition, LA slightly weakens copper-induced smooth eye phenotype when amyloid-β protein precursor (AβPP) and beta-site AβPP cleaving enzyme 1 (BACE1) are overexpressed in eye photoreceptor cells. CONCLUSION: Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Cell Line; Copper; Disease Models, Animal; Drosophila melanogaster; Humans; Neurons; Thioctic Acid

40 Hz Light Flicker Promotes Learning and Memory via Long Term Depression in Wild-Type Mice. - Tian, Tian; Qin, Xin; Wang, Yali; Shi, Yan; Yang, Xin (J Alzheimers Dis, 2021)
BACKGROUND: 40 Hz light flicker is a well-known non-invasive treatment that is thought to be effective in treating Alzheimer's disease. However, the effects of 40 Hz visual stimulation on neural networks, synaptic plasticity, and learning and memory in wild-type animals remain unclear. OBJECTIVE: We aimed to explore the impact of 40 Hz visual stimulation on synaptic plasticity, place cell, and learning and memory in wild-type mice. METHODS: c-Fos+ cell distribution and in vivo electrophysiology was used to explore the effects of 40 Hz chronic visual stimulation on neural networks and neuroplasticity in wild-type mice. The character of c-Fos+ distribution in the brain and the changes of corticosterone levels in the blood were used to investigate the state of animal. Place cell analysis and novel location test were utilized to examine the effects of 40 Hz chronic visual stimulation on learning and memory in wild-type mice. RESULTS: We found that 40 Hz light flicker significantly affected many brain regions that are related to stress. Also, 40 Hz induced gamma enrichment within 15 min after light flickers and impaired the expression of long-term potentiation (LTP), while facilitated the expression of long-term depression (LTD) in the hippocampal CA1. Furthermore, 40 Hz light flicker enhanced the expression of corticosterone, rendered well-formed place cells unstable and improved animal's learning and memory in novel local recognition test, which could be blocked by pre-treatment with the LTD specific blocker Glu2A-3Y. CONCLUSION: These finding suggested that 40 Hz chronic light flicker contains stress effects, promoting learning and memory in wild-type mice via LTD.

Accelerometer-Measured, Habitual Physical Activity and Circulating Brain-Derived Neurotrophic Factor: A Cross-Sectional Study. - Spartano, Nicole L; Himali, Jayandra J; Trinquart, Ludovic; Yang, Qiong; Weinstein, Galit; Satizabal, Claudia L; Dukes, Kimberly A; Beiser, Alexa S; Murabito, Joanne M; Vasan, Ramachandran S; Seshadri, Sudha (J Alzheimers Dis, 2021)
BACKGROUND: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels. OBJECTIVE: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort. METHODS: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement and platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time. RESULTS: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p > 0.05). We observed a non-linear trend, where 15-50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (β= -0.049±0.024, p = 0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (β= -0.216±0.079, p = 0.01). CONCLUSION: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA.

Is Acculturation Associated with the Cognitive Performance of Older Hispanics? - Alam, Rifat B; Singleton, Chelsea R; Aguiñaga, Susan; Chodzko-Zajko, Wojtek; Jahan, Nilufer A; Oke, Adeyosola; Schwingel, Andiara (J Alzheimers Dis, 2021)
BACKGROUND: Hispanics in the United Statues are disproportionately affected by Alzheimer's disease and related dementias. Little is known about the impact of acculturation on cognitive performance. OBJECTIVE: This study examined the association between acculturation and cognitive performance among older Hispanics. METHODS: We analyzed cross-sectional data of 616 Hispanic participants in the National Health and Nutrition Examination Survey (NHANES) 2011-2014 [average age = 67.15 years, %Female = 51.46, %less than high-school graduate = 52.60]. Cognitive performance was measured by two neuropsychological tests: Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST). We used two single-item proxy measures to quantify acculturation: nativity status (non-US-born residing <  15 years in the US (low acculturation), non-US-born residing ≥15 years in the US, and US-born (high acculturation)); and language acculturation (only/mostly Spanish (low acculturation), Spanish and English, only/mostly English (high acculturation)). We used adjusted linear regression to evaluate associations between acculturation and cognitive performance. RESULTS: Results indicated poorer cognitive performance among the low-acculturated groups for both nativity and linguistic measures. Participants who were non-US-born living ≥15 years (p = 0.02) and speaking only/mostly Spanish or Spanish and English (p = 0.01 and 0.006 respectively) had significantly lower AFT scores compared to US-born and only/mostly English-speaking groups. Participants who were non-US-born living <  15 years (p <  0.0001) or non-US-born living ≥15 years (p <  0.0001) and speaking only/mostly Spanish (p = 0.0008) scored lower on the DSST than the US-born and only/mostly English-speaking participants. CONCLUSION: In summary, low acculturation is associated with poorer cognitive performance among older Hispanics. Acculturation might be an important attribute to help understand cognitive decline and dementias among Hispanics.

Acute Exercise and Cognitive Function in Alzheimer's Disease. - Ben Ayed, Ines; Castor-Guyonvarch, Naomie; Amimour, Souad; Naija, Salma; Aouichaoui, Chirine; Ben Omor, Sana; Tabka, Zouhair; El Massioui, Farid (J Alzheimers Dis, 2021)
BACKGROUND: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer's disease (ADM) patients. OBJECTIVE: Evaluating the effect of AAE on cognitive functions in ADM patients. METHODS: Overall, 79 (age: 69.62±0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted of a 20-min cycling exercise of moderate intensity, corresponding to 60%of the individual target maximal heart rate recorded in a 6-minute walking test. The participants' cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks. RESULTS: After the exercise, the participants' attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session. CONCLUSION: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients.

Alzheimer's Disease and Face Masks in Times of COVID-19. - Gil, Roger; Arroyo-Anlló, Eva M (J Alzheimers Dis, 2021)
Generalized lockdown caused by COVID-19, necessary yesterday, can no longer be that of tomorrow. It will no longer be possible to cram the humblest into cramped areas, but priority must be given to prevention (certainly with physical barriers, hydro-alcoholic gel, face masks), biological diagnosis, isolation, and also the care of any infected person. COVID-19 has hit the most vulnerable first in terms of biological inequality, such as Alzheimer's disease (AD) patients. Those with AD can have sensorial deficits and perception troubles, including visual difficulties and the inability to recognize faces and emotions. Face masks and physical distancing can disrupt facial familiarity and make it more difficult to recognize emotional facial expressions. It can provoke distress, which the visitor can perceive and feel obligated to take off the face mask. This gesture should not be considered as an act of indiscipline, but an act of empathy. Transparent face masks could improve the suffering of AD patients, distraught in the presence of their loved ones whose masks hide their faces. Wearing a mask should not be due to fear of punishment, but as an understanding of the responsibility of each individual in the control of the current pandemic. It may be necessary to convince more citizens of this civic duty, using clear and attractive messaging in order to standardize the wearing of face masks for the general public and to adapt them to the needs of patients.
Keywords: Alzheimer Disease; Communicable Disease Control; COVID-19; Emotions; Facial Expression; Humans; Masks

Alzheimer's Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort. - Barthold, Douglas; Gibbons, Laura E; Marcum, Zachary A; Gray, Shelly L; Dirk Keene, C; Grabowski, Thomas J; Postupna, Nadia; Larson, Eric B; Crane, Paul K (J Alzheimers Dis, 2021)
BACKGROUND: Diabetes is a risk factor for Alzheimer's disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). OBJECTIVE: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. METHODS: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1-42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. RESULTS: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1-42 (-0.57 (CI: -1.12, -0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1-42 compared to nonusers (-0.15 (CI: -0.28, -0.02), -0.31 (CI: -0.54, -0.07), respectively). CONCLUSION: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1-42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

Amyloid Deposition Is Greater in Cerebral Gyri than in Cerebral Sulci with Worsening Clinical Diagnosis Across the Alzheimer's Disease Spectrum. - Walden, Lucas M; Hu, Song; Madabhushi, Anant; Prescott, Jeffrey W (J Alzheimers Dis, 2021)
BACKGROUND: Histopathologic studies have demonstrated differential amyloid-β (Aβ) burden between cortical sulci and gyri in Alzheimer's disease (AD), with sulci having a greater Aβ burden. OBJECTIVE: To characterize Aβ deposition in the sulci and gyri of the cerebral cortex in vivo among subjects with normal cognition (NC), mild cognitive impairment (MCI), and AD, and to evaluate if these differences could improve discrimination between diagnostic groups. METHODS: T1-weighted 3T MR and florbetapir (amyloid) positron emission tomography (PET) data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). T1 images were segmented and the cortex was separated into sulci/gyri based on pial surface curvature measurements. T1 images were registered to PET images and regional standardized uptake value ratios (SUVr) were calculated. A linear mixed effects model was used to analyze the relationship between clinical variables and amyloid PET SUVr measurements in the sulci/gyri. Receiver operating characteristic (ROC) analysis was performed to define amyloid positivity. Logistic models were used to evaluate predictive performance of clinical diagnosis using amyloid PET SUVr measurements in sulci/gyri. RESULTS: 719 subjects were included: 272 NC, 315 MCI, and 132 AD. Gyral and sulcal Aβ increased with worsening cognition, however there was a greater increase in gyral Aβ. Females had a greater gyral and sulcal Aβ burden. Focusing on sulcal and gyral Aβ did not improve predictive power for diagnostic groups. CONCLUSION: While there were significant differences in Aβ deposition in cerebral sulci and gyri across the AD spectrum, these differences did not translate into improved prediction of diagnosis. Females were found to have greater gyral and sulcal Aβ burden.

ANMerge: A Comprehensive and Accessible Alzheimer's Disease Patient-Level Dataset. - Birkenbihl, Colin; Westwood, Sarah; Shi, Liu; Nevado-Holgado, Alejo; Westman, Eric; Lovestone, Simon; Hofmann-Apitius, Martin (J Alzheimers Dis, 2021)
BACKGROUND: Accessible datasets are of fundamental importance to the advancement of Alzheimer's disease (AD) research. The AddNeuroMed consortium conducted a longitudinal observational cohort study with the aim to discover AD biomarkers. During this study, a broad selection of data modalities was measured including clinical assessments, magnetic resonance imaging, genotyping, transcriptomic profiling, and blood plasma proteomics. Some of the collected data were shared with third-party researchers. However, this data was incomplete, erroneous, and lacking in interoperability. OBJECTIVE: To provide the research community with an accessible, multimodal, patient-level AD cohort dataset. METHODS: We systematically addressed several limitations of the originally shared resources and provided additional unreleased data to enhance the dataset. RESULTS: In this work, we publish and describe ANMerge, a new version of the AddNeuroMed dataset. ANMerge includes multimodal data from 1,702 study participants and is accessible to the research community via a centralized portal. CONCLUSION: ANMerge is an information rich patient-level data resource that can serve as a discovery and validation cohort for data-driven AD research, such as, for example, machine learning and artificial intelligence approaches.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cohort Studies; Datasets as Topic; Female; Gene Expression Profiling; Genotype; Humans; Magnetic Resonance Imaging; Male; Proteomics

Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer's Disease. - Bastrup, Joakim; Hansen, Kathrine H; Poulsen, Thomas B G; Kastaniegaard, Kenneth; Asuni, Ayodeji A; Christensen, Søren; Belling, Dorthe; Helboe, Lone; Stensballe, Allan; Volbracht, Christiane (J Alzheimers Dis, 2021)
BACKGROUND: Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently. OBJECTIVE: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg). METHODS: After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient. RESULTS: In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice. CONCLUSION: We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antibodies, Monoclonal, Humanized; Brain; Chromatography, Liquid; Cytoskeletal Proteins; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Mitochondrial Proteins; Plaque, Amyloid; Presenilin-1; Protein Transport; Proteome; Proteomics; Stress, Physiological; Tandem Mass Spectrometry

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid. - Berger, Miles; Cooter, Mary; Roesler, Alexander S; Chung, Stacey; Park, John; Modliszewski, Jennifer L; VanDusen, Keith W; Thompson, J Will; Moseley, Arthur; Devinney, Michael J; Smani, Shayan; Hall, Ashley; et al. (J Alzheimers Dis, 2021)
BACKGROUND: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. OBJECTIVE: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. METHODS: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. RESULTS: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. CONCLUSION: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.
Keywords: Aged; Alzheimer Disease; Apolipoprotein E4; Biomarkers; Chitinase-3-Like Protein 1; DNA Copy Number Variations; Female; Fructose-Bisphosphate Aldolase; Humans; Male; Proteomics; Receptors, Immunologic

Apolipoprotein E ɛ4 (APOE ɛ4) Allele is Associated with Long Sleep Duration Among Elderly with Cognitive Impairment. - Basta, Maria; Zaganas, Ioannis; Simos, Panagiotis; Koutentaki, Eirini; Dimovasili, Christina; Mathioudakis, Lambros; Bourbouli, Mara; Panagiotakis, Symeon; Kapetanaki, Stefania; Vgontzas, Alexandros (J Alzheimers Dis, 2021)
BACKGROUND: Apolipoprotein E gene (APOE) ɛ4 allele increases the risk for Alzheimer's disease (AD). Furthermore, among patients with cognitive impairment, longer sleep duration is associated with worse cognitive performance. To date, literature examining the associations between APOE ɛ4 allele and objective sleep duration is limited. OBJECTIVE: Our aim was to assess the association between APOE ɛ4 and objective sleep duration, among patients with mild cognitive impairment (MCI) and AD. A sub-sample of 89 patients with AD (n = 49) and MCI (n = 40) were recruited from a large, population-based cohort of 3,140 elders (>60 years) residing on Crete, Greece. METHODS: All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and APOE ɛ4 allele genotyping. Comparisons of sleep duration variables between APOE ɛ4 allele carriers and non-carriers were assessed using ANCOVA, controlling for confounders. RESULTS: The sample included 18 APOE ɛ4 carriers and 71 non-carriers, aged 78.6±6.6 and 78.2±6.5 years, respectively. Comparisons between the APOE ɛ4 carriers and non-carriers revealed no significant differences in terms of demographic and clinical variables. In terms of objective sleep duration across the two groups, APOE ɛ4 carriers compared to non-carriers had significantly longer nighttime Total Sleep Time (nTST) (7.7±1.4 versus 7.2±1.3  h, respectively, p = 0.011), as well as 24 h TST (8.5±1.6 versus 7.8±1.5  h, respectively, p = 0.012). CONCLUSION: Among patients with MCI and AD, APOE ɛ4 carriers have longer objective nighttime and 24 h sleep duration compared to non-carriers. These findings further support that objective long sleep duration is a genetically-driven pre-clinical marker associated with worse prognosis in elderly with cognitive impairment.

Assessing the Progression of Alzheimer's Disease in Real-World Settings in Three European Countries. - Lladó, Albert; Froelich, Lutz; Khandker, Rezaul K; Roset, Montserrat; Black, Christopher M; Lara, Nuria; Chekani, Farid; Ambegaonkar, Baishali M (J Alzheimers Dis, 2021)
BACKGROUND: There exists considerable variation in disease progression rates among patients with Alzheimer's disease (AD). OBJECTIVE: The primary objective of this observational study is to assess the progression of AD by characterizing cognitive, functional, and behavioral changes during the follow-up period between 6 and 24 months. METHODS: A longitudinal prospective study with community-dwelling patients with an established clinical diagnosis of AD of mild to moderate severity was conducted in Germany, Spain and the UK. A sample of 616 patients from 69 sites was included. RESULTS: Patients had a mean of 1.9 years (SD = 1.9) since AD diagnosis at study inclusion. Cognitive symptoms were reported to have first occurred a mean of 1.1 years (SD = 1.7) prior to AD diagnosis and 1.4 (SD = 1.8) years prior to AD treatment. Patients initially diagnosed with mild and moderate AD spent a median (95%CI) of 3.7 (2.8; 4.4) and 11.1 (6.1, 'not reached') years until progression to moderate and severe AD, respectively, according to the Mini-Mental State Examination (MMSE) scores. A mixed model developed for cognitive, functional, and neuropsychiatric scores, obtained from study patients at baseline and during follow-up period, showed progressive deterioration of AD patients over time. CONCLUSION: The study showed a deterioration of cognitive, functional, and neuropsychiatric functions during the follow-up period. Cognitive deterioration was slightly faster in patients with moderate AD compared to mild AD. The duration of moderate AD can be overestimated due to the use of retrospective data, lack of availability of MMSE scores in clinical charts and exclusion of patients at time of institutionalization.
Keywords: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Europe; Germany; Humans; Institutionalization; Neuropsychological Tests; Spain

Association Between Elevated Depressive Symptoms and Cognitive Function Moderated by APOE4 Status: Framingham Offspring Study. - Piers, Ryan J; Liu, Yulin; Ang, Ting F A; Tao, Qiushan; Au, Rhoda; Qiu, Wei Qiao (J Alzheimers Dis, 2021)
BACKGROUND: Depression and Apolipoprotein E4 (APOE4) are associated with decreased cognitive function and differences in brain structure. OBJECTIVE: This study investigated whether APOE4 status moderates the association between elevated depressive symptoms, cognitive function, and brain structure. METHODS: Stroke- and dementia-free participants (n = 1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status. RESULTS: Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4 + participants. Elevated depressive symptoms were not associated with any brain structure in this study sample. CONCLUSION: Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4 + .

The Association Between Homocysteine and Memory in Older Adults. - Nelson, Monica E; Andel, Ross; Nedelska, Zuzana; Martinkova, Julie; Cechova, Katerina; Marková, Hana; Matuskova, Veronika; Nikolai, Tomas; Lerch, Ondřej; Pařízková, Martina; Laczó, Jan; Vyhnálek, Martin; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Identifying modifiable risk factors for cognitive decline can reduce burden of dementia. OBJECTIVE: We examined whether homocysteine was associated with memory performance, mediated by entorhinal volume, hippocampal volume, total gray matter volume, or white matter lesions, and moderated by APOE ɛ4 allele, B vitamins, creatinine, total cholesterol, or triglycerides. METHODS: All 204 members of the Czech Brain Aging Study with subjective cognitive decline (SCD; n = 60) or amnestic mild cognitive impairment (aMCI; n = 144) who had valid data were included. Linear regression was used, followed by conditional process modeling to examine mediation and moderation. RESULTS: Controlling for age, sex, and education, higher homocysteine was related to poorer memory performance overall (b = -0.03, SE = 0.01, p = 0.017) and in participants with SCD (b = -0.06, SE = 0.03, p = 0.029), but less so in aMCI (b = -0.03, SE = 0.02, p = 0.074); though sensitivity analyses revealed a significant association when sample was reduced to aMCI patients with more complete cognitive data (who were also better functioning; b = -0.04, SE = 0.02, p = 0.022). Results were unchanged in fully adjusted models. Neither mediation by markers of brain integrity nor moderation by APOE ɛ4, B vitamins, creatinine, and cardiovascular factors were significant. Memory sub-analyses revealed that results for SCD were likely driven by non-verbal memory. The homocysteine-memory relationship was significant when hippocampal volume was below the median (b = -0.04, SE = 0.02, p = 0.046), but not at/above the median (p = 0.247). CONCLUSION: Higher homocysteine levels may adversely influence memory performance, particularly in those without cognitive impairment. Results appear to be independent of brain health, suggesting that homocysteine may represent a good target for intervention.

Association Between the APOEɛ2/ɛ4 Genotype and Alzheimer's Disease and Mild Cognitive Impairment Among African Americans. - Ren, Dianxu; Lopez, Oscar L; Lingler, Jennifer H; Conley, Yvette (J Alzheimers Dis, 2021)
We examined the association between APOEɛ2/ɛ4 with incident Alzheimer's disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer's Coordinating Center (NACC) from 2005 to September 2019. Compared to ɛ3/ɛ3 carriers, ɛ2/ɛ4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOEɛ2/ɛ4 genotype is not associated with the incidence of AD and MCI among African Americans.

Association of Amyloid-β Pathology with Decision Making and Scam Susceptibility. - Kapasi, Alifiya; Yu, Lei; Stewart, Christopher; Schneider, Julie A; Bennett, David A; Boyle, Patricia A (J Alzheimers Dis, 2021)
BACKGROUND: Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer's disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia. METHODS: Data came from 198 deceased participants without clinical dementia (mean age at death = 90 years; 69%women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-β and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy. RESULTS: In linear regression models adjusted for demographics, amyloid-β pathology was associated with lower decision making (estimate = -0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = -0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02). CONCLUSION: Accumulating AD pathology, particularly amyloid-β, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.

The Association of Essential Metals with APOE Genotype in Alzheimer's Disease. - Babić Leko, Mirjana; Jurasović, Jasna; Nikolac Perković, Matea; Španić, Ena; Sekovanić, Ankica; Orct, Tatjana; Lukinović Škudar, Vesna; Bačić Baronica, Koraljka; Kiđemet-Piskač, Spomenka; Vogrinc, Željka; Pivac, Nela; Borovečki, Fran; et al. (J Alzheimers Dis, 2021)
BACKGROUND: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer's disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. OBJECTIVE: To test the association of essential metals with APOE genotype. METHODS: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. RESULTS: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. CONCLUSION: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

Association of Malnutrition with Functional and Cognitive Trajectories in People Living with Dementia: A Five-Year Follow-Up Study. - Borda, Miguel Germán; Ayala Copete, Ana María; Tovar-Rios, Diego Alejandro; Jaramillo-Jimenez, Alberto; Giil, Lasse Melvær; Soennesyn, Hogne; Gómez-Arteaga, Camilo; Venegas-Sanabria, Luis Carlos; Kristiansen, Ida; Chavarro-Carvajal, Diego Andrés; Caicedo, Sandra; Cano-Gutierrez, Carlos Alberto; et al. (J Alzheimers Dis, 2021)
BACKGROUND: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. OBJECTIVE: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. METHODS: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer's disease (AD) (n = 103), Lewy body dementia (LBD) (n = 74), and other dementias (OD) (n = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. RESULTS: At baseline, the prevalence of general malnutrition was 28.7%; 17.32% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. CONCLUSION: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis.

Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study. - Gonzales, Mitzi M; Samra, Jasmeet; O'Donnell, Adrienne; Mackin, R Scott; Salinas, Joel; Jacob, Mini; Satizabal, Claudia L; Aparicio, Hugo J; Thibault, Emma G; Sanchez, Justin S; Finney, Rebecca; Rubinstein, Zoe B; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012). CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

Association of White Matter Hyperintensity Progression with Cognitive Decline in Patients with Amnestic Mild Cognitive Impairment. - Hirao, Kentaro; Yamashita, Fumio; Tsugawa, Akito; Haime, Rieko; Fukasawa, Raita; Sato, Tomohiko; Kanetaka, Hidekazu; Umahara, Takahiko; Sakurai, Hirofumi; Hanyu, Haruo; Shimizu, Soichiro (J Alzheimers Dis, 2021)
BACKGROUND: White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date. OBJECTIVE: To investigate the association between WMH progression and cognitive decline in amnestic MCI patients. METHODS: Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated. RESULTS: An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item. CONCLUSION: DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

Automatic Subtyping of Individuals with Primary Progressive Aphasia. - Themistocleous, Charalambos; Ficek, Bronte; Webster, Kimberly; den Ouden, Dirk-Bart; Hillis, Argye E; Tsapkini, Kyrana (J Alzheimers Dis, 2021)
BACKGROUND: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. OBJECTIVE: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA. METHODS: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians' classifications. RESULTS: The DNN model outperformed the other machine learning models as well as expert clinicians' classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants. CONCLUSION: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA.
Keywords: Acoustics; Aged; Aphasia, Primary Progressive; Decision Trees; Female; Humans; Linguistics; Machine Learning; Male; Models, Theoretical; Neural Networks, Computer; Primary Progressive Nonfluent Aphasia; Reproducibility of Results; Support Vector Machine

B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment. - Jakubowski, Hieronim; Zioła-Frankowska, Anetta; Frankowski, Marcin; Perła-Kaján, Joanna; Refsum, Helga; de Jager, Celeste A; Smith, A David (J Alzheimers Dis, 2021)

The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation. - Dekker, Alain D; Ulgiati, Aurora M; Groen, Henk; Boxelaar, Vincent A; Sacco, Silvia; Falquero, Ségolène; Carfi, Angelo; di Paola, Antonella; Benejam, Bessy; Valldeneu, Silvia; Fopma, Roelie; Oosterik, Marjo; et al. (J Alzheimers Dis, 2021)
BACKGROUND: People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior. OBJECTIVE: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population. METHODS: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113). RESULTS: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising. CONCLUSION: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.
Keywords: Adult; Aged; Anxiety; Dementia; Down Syndrome; Female; Humans; Irritable Mood; Male; Middle Aged; Reproducibility of Results; Symptom Assessment

Bile Acids as Key Modulators of the Brain-Gut-Microbiota Axis in Alzheimer's Disease. - Mulak, Agata (J Alzheimers Dis, 2021)
Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer's disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affect gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. An age-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists.
Keywords: Alzheimer Disease; Bile Acids and Salts; Brain-Gut Axis; Humans; Neuroprotection; Signal Transduction

Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein. - Quint, Wim Hendricus; Matečko-Burmann, Irena; Schilcher, Irene; Löffler, Tina; Schöll, Michael; Burmann, Björn Marcus; Vogels, Thomas (J Alzheimers Dis, 2021)
BACKGROUND: Alzheimer's disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson's disease and Lewy body dementia also frequently occur together with tau pathology. OBJECTIVE: Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway. METHODS: Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q. RESULTS: Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway. CONCLUSION: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

Blood-Based ATN Biomarkers of Alzheimer's Disease: A Meta-Analysis. - Koychev, Ivan; Jansen, Katrin; Dette, Alina; Shi, Liu; Holling, Heinz (J Alzheimers Dis, 2021)
BACKGROUND: The Amyloid Tau Neurodegeneration (ATN) framework was proposed to define the biological state underpinning Alzheimer's disease (AD). Blood-based biomarkers offer a scalable alternative to the costly and invasive currently available biomarkers. OBJECTIVE: In this meta-analysis we sought to assess the diagnostic performance of plasma amyloid (Aβ40, Aβ42, Aβ42/40 ratio), tangle (p-tau181), and neurodegeneration (total tau [t-tau], neurofilament light [NfL]) biomarkers. METHODS: Electronic databases were screened for studies reporting biomarker concentrations for AD and control cohorts. Biomarker performance was examined by random-effect meta-analyses based on the ratio between biomarker concentrations in patients and controls. RESULTS: 83 studies published between 1996 and 2020 were included in the analyses. Aβ42/40 ratio as well as Aβ42 discriminated AD patients from controls when using novel platforms such as immunomagnetic reduction (IMR). We found significant differences in ptau-181 concentration for studies based on single molecule array (Simoa), but not for studies based on IMR or ELISA. T-tau was significantly different between AD patients and control in IMR and Simoa but not in ELISA-based studies. In contrast, NfL differentiated between groups across platforms. Exosome studies showed strong separation between patients and controls for Aβ42, t-tau, and p-tau181. CONCLUSION: Currently available assays for sampling plasma ATN biomarkers appear to differentiate between AD patients and controls. Novel assay methodologies have given the field a significant boost for testing these biomarkers, such as IMR for Aβ, Simoa for p-tau181. Enriching samples through extracellular vesicles shows promise but requires further validation.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Humans; Neurodegenerative Diseases; Neurofibrillary Tangles; Neurofilament Proteins; Peptide Fragments; Phosphorylation; Plaque, Amyloid; tau Proteins

Body Mass Index and Mild Cognitive Impairment Among Middle-Aged and Older Adults from Low- and Middle-Income Countries. - Smith, Lee; Shin, Jae Il; Oh, Hans; Carmichael, Christina; Jacob, Louis; Stefanac, Sinisa; Lindsay, Rosie K; Soysal, Pinar; Veronese, Nicola; Tully, Mark A; Butler, Laurie; Barnett, Yvonne; et al. (J Alzheimers Dis, 2021)
BACKGROUND: The effect of weight modification on future dementia risk is currently a subject of debate and may be modified by age. OBJECTIVE: The aim of the present study was to investigate the association between body mass index (BMI) status with mild cognitive impairment (MCI) (a preclinical stage of dementia) in middle-aged and older adults residing in six low- and middle-income countries using nationally representative data. METHODS: Cross-sectional data from the Study on Global Ageing and Adult Health (SAGE) were analyzed. MCI was defined using the National Institute on Aging-Alzheimer's Association criteria. BMI (kg/m2) was based on measured weight and height and categorized as: underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). Multivariable logistic regression analysis and meta-analysis were conducted to assess associations. RESULTS: Data on 32,715 individuals aged ≥50 years with preservation in functional abilities were analyzed [mean (SD) age 62.1 (15.6) years; 51.7% females]. Among those aged 50-64 years, compared to normal weight, underweight (OR = 1.44; 95% CI = 1.14-1.81), overweight (OR = 1.17; 95% CI = 1.002-1.37), and obesity (OR = 1.46; 95% CI = 1.09-1.94) were all significantly associated with higher odds for MCI. In those aged ≥65 years, underweight (OR = 0.71; 95% CI = 0.54-0.95) and overweight (OR = 0.72; 95% CI = 0.55-0.94) were associated with significantly lower odds for MCI, while obesity was not significantly associated with MCI. CONCLUSION: The results of the study suggest that the association between BMI and MCI is likely moderated by age. Future longitudinal studies are required to confirm or refute the present findings before recommendations for policy and practice can be made.