Review
Huan Wang#, Ning Qin#, Dilinuer Maimaitiaili#, Jiali Wu, Shuangqin Wang, Yixin Zhou, Jingjue Lu, Yuanli Li #These authors contributed equally to this work.
Transcranial electrical stimulation as a therapeutic strategy for Alzheimer’s disease: Current uses and challenges
Abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disorder for which there are currently rarely effective drug treatments available to halt or slow down its progression. With the aging of the world population, AD as the primary cause of dementia, is rapidly becoming one of the most expensive, lethal, and burdening diseases of this century. In recent years, the new method used to treat nervous system diseases including AD is transcranial electrical stimulation (tES) with non-invasive and for regulating the flexibility of neural circuits operation and behaviors. The rationale of tES for AD neuromodulation is derived from research on animal and clinical trials. In the present paper, we review the current uses of the tES including transcranial direct current stimulation, transcranial alternating current stimulation, and transcranial pulsed electrical stimulation in rehabilitation for AD’s core clinical symptom with cognitive dysfunctions, as well as the relevant data from AD animal models have also been discussed. Finally, the regarding applied challenges of tES in AD therapy have been referred for further improvement.
Review
Amnah A. Alharbi, Hanan E Alatwi, Hana Albulaihe, Norah K Algarzae
Alzheimer’s disease in the Kingdom of Saudi Arabia: Current perspectives and genetic insights
Abstract: The prevalence of dementia and mild cognitive disorder has markedly risen in recent years. Alzheimer’s disease (AD) stands out as the most common form of neurodegenerative dementia among the elderly, featuring progressive memory loss and cognitive decline. Although the exact biological causes of AD are complex and multifactorial, genetics is considered a prominent contributor. To date, around 80 genetic loci have been identified, primarily in European ancestry groups, though a considerable portion of AD's genetic architecture remains elusive. Recognizing the impending rise in AD cases, both governmental and private sectors in Saudi Arabia are making efforts to enhance formal care and services for older adults. While few studies have investigated AD-susceptible genes within the Saudi population, further attention is needed to explore the genetic background and identify molecular biomarkers associated with AD. This review provides an overview of the current understanding of AD and recent genetic research in Saudi Arabia.
Short Communication
Inbal Mayan, Heidi Roth, Dhrubajyoti Ghosh, Heather E Whitson, Kim G Johnson
Genetic and biomarker disclosure process in a memory and aging study
Abstract: Despite growing awareness that disclosing biomarker results to research participants is aligned with ethical principles of researcher-participant partnership, there are currently no widely adopted guidelines for this disclosure in Alzheimer's disease research. We developed a process and tools to deliver biomarker and genetic results to 65 participants of The Memory and Aging Study of the Duke-UNC Alzheimer’s Disease Research Center (ADRC). Survey responses of 46 participants were analyzed. We show high participant satisfaction and lower anxiety levels after receiving the results. The developed process and materials provide a template for standardized Alzheimer’s disease biomarker result delivery in the research setting.
Short Communication
Hiroo Kasahara, Masaki Ikeda, Kouki Makioka, Takumi Nakamura, Ryoma Takahashi, Takeshi Kawarabayashi, Etsuko Sanada, Takayuki Suto, Tetsuya Higuchi, Yoshito Tsushima, Yoshio Ikeda
White matter lesions rather than amyloid-β burden are associated with cognitive decline in Alzheimer’s disease
Abstract: We assessed the severity of amyloid-β accumulation and white matter lesions (WML) in the brain, and their association with cognitive decline, in patients (n = 47) with Alzheimer's disease (AD). The mean cortical standardized uptake value ratio (mcSUVR) was derived from amyloid positron emission tomography, while the percentage of WML area relative to brain parenchymal area was determined using magnetic resonance imaging. Cognitive decline was positively correlated with WML severity (r = 0.50, p = 0.042) but not mcSUVR (Aβ accumulation). Managing vascular risk factors can prevent cognitive decline in patients with AD.
Short Communication
Thanapoom Taweephol, Thanakit Pongpitakmetha, Kittithatch Booncharoen, Jedsada Khieukhajee, Watayuth Luechaipanit, Thanaporn Haethaisong, Adipa Chongsuksantikul, Yuttachai Likitjaroen, Poosanu Thanapornsangsuth
Evaluating roles of plasma glial fibrillary acidic protein as Alzheimer’s disease biomarker in real-world multi-center memory clinics in Thailand
Abstract: The roles of reactive astrocytes in Alzheimer’s disease (AD) and the correlation between plasma glial fibrillary acidic protein (GFAP) and amyloid-β are emerging. Among 133 patients with cognitive complaints from multi-center memory clinics in Thailand, 73 had AD as defined either by cerebrospinal fluid core biomarkers or amyloid PET. Plasma GFAP demonstrated an AUC of 0.74 (95%CI: 0.65-0.83) for detecting AD and showed large effects on identifying AD status with Cohen’s d = 0.81 (95%CI 0.44-1.18). LOESS regression illustrated that plasma GFAP increased from the early stages of AD. Plasma GFAP has potential applications across diverse populations.
Commentary
Rhuann Pontes dos Santos Silva, Breno José Alencar Pires Barbosa
Exploring the potential of acupuncture as a complementary treatment for Alzheimer’s disease: Pushing the boundaries forward
Abstract: Acupuncture has emerged as a promising adjunctive symptomatic therapy for Alzheimer's disease, demonstrating potential benefits in cognitive function and neuroprotection. Recent meta-analyses and randomized clinical trials have investigated the potential of acupuncture to improve cognitive assessments, signaling pathways, and gut regulation in Alzheimer’s disease, underscoring its potential clinical application. However, the limited number of studies, small sample sizes, and lack of detailed mapping of acupuncture's core targets must be considered when interpreting these positive results.
Commentary
Jie Shao, Hannah Youngblood, Luodan Yang
Targeting SPI1 to mitigate amyloid-β pathology in Alzheimer’s disease
Abstract: SPI1, a transcription factor implicated in myeloid cell development, has emerged as a genetic risk factor for Alzheimer’s disease (AD). Recent in vivo studies reveal that Spi1 knockdown in mice exacerbates AD pathology by increasing amyloid-β aggregation and gliosis while Spi1 overexpression ameliorates these features. Transcriptomic analyses suggest that Spi1 regulates microglial immune response, complement activation, and phagocytosis. SPI1 regulation of these processes may explain how SPI1 affects AD risk. Further studies, including human validation, are needed to explore the dynamic influence of SPI1 across AD stages, its applicability to clinical settings, and its potential as a therapeutic target.
Marco Michelutti#, Daniele Urso#, Benedetta Tafuri, Valentina Gnoni, Alessia Giugno, Chiara Zecca, Maria Teresa Dell’Abate, Davide Vilella, Paolo Manganotti, Roberto De Blasi, Salvatore Nigro, Giancarlo Logroscino #These authors contributed equally to this work.
Structural covariance network patterns linked to neuropsychiatric symptoms in biologically defined Alzheimer’s disease: Insights from the Mild Behavioral Impairment Checklist
Abstract: Background: The frequent presentation of Alzheimer’s disease (AD) with neuropsychiatric symptoms (NPS) in the context of normal or minimally-impaired cognitive function led to the concept of Mild Behavioral Impairment (MBI). While MBI's impact on subsequent cognitive decline is recognized, its association with brain network changes in biologically-defined AD remains unexplored. Objective: To investigate the correlation of structural covariance networks with MBI-C checklist sub-scores in biologically-defined AD patients. Methods: We analyzed 33 biologically-defined AD patients, ranging from mild cognitive impairment to early dementia, all characterized as amyloid-positive through cerebrospinal fluid analysis or amyloid positron emission tomography scans. Regional network properties were assessed through graph theory. Results: Affective dysregulation correlated with decreased segregation and integration in the right inferior frontal gyrus (IFG). Impulse dyscontrol and social inappropriateness correlated positively with centrality and efficiency in the right posterior cingulate cortex (PCC). Global network properties showed a preserved small-world organization. Conclusions: This study reveals associations between MBI subdomains and structural brain network alterations in biologically-confirmed AD. The IFG's involvement is crucial for mood dysregulation, while the PCC could be involved in compensatory mechanisms for social cognition and impulse control. These findings underscore the significance of biomarker-based neuroimaging for the characterization of NPS across the AD spectrum.
Marta Stojanovic, Peter R Millar, Nicole S McKay, Andrew J Aschenbrenner, David A Balota, Jason Hassenstab, Tammie LS Benzinger, John C Morris, Beau M Ances
The associations between attentional control, episodic memory, and Alzheimer’s disease biomarkers of tau and neurodegeneration
Abstract: Background: While episodic memory decline is the most common cognitive symptom of Alzheimer’s disease (AD), changes in attentional control have also been found to be sensitive to early AD pathology. The relations between longitudinal trajectories of these specific cognitive domains, especially attentional control, and biomarkers of tau and neurodegeneration have not been thoroughly examined. Objective: We examined whether baseline tau positron emission tomography (PET) and cortical thickness, relatively later markers within the AD cascade, predicted cross-sectional and longitudinal changes in episodic memory and attentional control. Methods: Cognitively normal individuals ([Clinical Dementia Rating CDR®]=0; n=249) at baseline completed a magnetic resonance imaging (MRI), tau PET, and multiple assessments of episodic memory and attentional control. Generalized additive models examined whether tau PET summary measure and cortical thickness signature predicted cross-sectional and longitudinal trajectories of attentional control and episodic memory. Results: Higher tau PET and lower MRI cortical thickness were generally associated with worse cross-sectional cognitive performance. Our exploratory analyses found cortex-wide associations between tau PET and episodic memory, with limited suggestions of region-specific associations with attentional control. On longitudinal follow-up, higher tau PET was associated with a greater decline in episodic memory. Conclusions: These results indicate that tau PET is particularly sensitive to detecting longitudinal changes in episodic memory. This further informs relevant endpoints for clinical drug trials in cognitively normal individuals. Future studies might consider longer follow-ups and lag associations between changes in AD biomarkers and changes in cognition.
Jae-Won Jang, Seung-Hwan Lee, Taesu Kim, Eunju Lee, Sang Won Park, Na Young Yeo, Young-Ju Kim
Hearing loss and the risk of dementia: A longitudinal analysis of the Korean National Health Insurance Service Senior Cohort
Abstract: Background: Hearing loss is a potentially modifiable risk factor implicated in dementia, with recent research suggesting an association between age-related hearing degradation and dementia. Objective: This study aims to elucidate the relationship between hearing decline and dementia risk. Methods: We analyzed data from 511,953 subjects from the Korean National Health Insurance Service-Senior Cohort (2002–2008). After excluding those diagnosed with dementia in 2002, 511,935 subjects were included. Subjects with hearing loss between 2002 and 2008 were selected and matched with a control group without hearing impairment based on age and gender. Statistical analyses, including Pearson’s chi-squared test and the Cox proportional hazards model, were conducted, controlling for confounding variables such as household income and residential area. Subgroup analysis was also performed for Alzheimer's disease and vascular dementia. Results: Subjects with hearing loss had a 1.245 times higher risk of all-cause dementia compared to those without hearing loss (adjusted hazard ratio over 3 years, 95% CI = 1.201–1.290), adjusting for gender, age, residence, and income. The adjusted hazard ratios for Alzheimer’s disease over 3, 5, 7, and 10 years from the index date were 1.259 (95% CI=1.211–1.308), 1.258 (95% CI=1.208–1.310), 1.269 (95% CI=1.215–1.325), and 1.235 (95% CI=1.170–1.304), respectively. No significant association was found for vascular dementia, except for 3 years. Conclusions: Hearing loss consistently increased the risk of all-cause dementia and Alzheimer’s disease across timespans, suggesting a complex link between hearing loss and neurodegenerative diseases. These findings highlight the importance of early intervention and cognitive monitoring for individuals with hearing loss.
Sami Heikkinen, Kasper Katisko, Annakaisa Haapasalo, Anne Portaankorva, Päivi Hartikainen, Eino Solje
Overlap in the diagnostic criteria of frontotemporal dementia syndromes with parkinsonism
Abstract: Background: Differentiating neurodegenerative diseases can be difficult in the clinical setting. This study examines the overlap of diagnostic criteria between frontotemporal dementia (FTD) syndromes with parkinsonism [e.g., corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), behavioral variant frontotemporal dementia (bvFTD)] and Parkinson's disease (PD). Objective: To explore the diagnostic overlap in patients with FTD syndromes with parkinsonism and PD. Methods: Patient records from 2751 individuals at a tertiary neurological care center were reviewed, resulting in 112 bvFTD, 38 PSP, and 15 CBS patients. Clinical features and diagnostic criteria fulfillment were assessed. Results: Significant overlap in diagnostic criteria fulfilment was found: 42 bvFTD and 22 PSP patients met possible CBS criteria, 6 bvFTD patients met possible PSP criteria, and 4 met criteria for all three conditions. Higher cerebrospinal fluid levels of phosphorylated tau and tau were observed in the bvFTD group compared to PSP (p = 0.009, p = 0.002). The Mini-Mental State Examination score also differed between bvFTD and PSP (p = 0.020), and between PSP and CBS (p = 0.047). Neuroimaging showed substantial heterogeneity. Conclusions: The study reveals significant overlap in diagnostic criteria among FTD syndromes with parkinsonism, underscoring the need for more precise diagnostic criteria. Improved biomarkers could support differential diagnosis and enhance clinical trial design. Common cerebrospinal fluid biomarkers used in Alzheimer’s disease diagnostics may provide additional support in the differential diagnosis.
Chen Wen, Jing‐Huan Gan, Shuai Liu, Hao Lu, Li-Chen Wang, Hao Wu, Zhi-Hong Shi, Yong Ji
Enlarged perivascular spaces correlate with blood-brain barrier leakage and cognitive impairment in Alzheimer’s disease
Abstract: Background: The clinical significance of enlarged perivascular spaces (EPVS) in Alzheimer’ s disease (AD) was ambiguous. Objective: To investigate whether EPVS contribute to blood-brain barrier (BBB) leakage and cognition in AD. Methods: The study included a total of 64 participants (26 healthy controls and 38 patients with AD). The evaluation of EPVS and BBB permeability was performed in specific anatomical locations: the centrum semiovale (CSO), basal ganglia, and hippocampus. The EPVS ratings were performed according to Potter's instructions. BBB permeability was evaluated using dynamic contrast-enhanced-MRI. The relationship between EPVS and global cognition (Mini-Mental State Examination and Montreal Cognitive Assessment), cognitive subdomains, and BBB permeability were examined in both groups. Finally, the relationship between CSO BBB permeability and cognition in AD patients was investigated. Results: High-grade CSO EPVS was found associated with AD (OR: 3.40, 95% CI: 1.11–11.90, p = 0.04). In the AD group, a significant correlation was observed between high-grade CSO EPVS and lower MMSE score (r = −0.36, p = 0.03) and verbal fluency (r = −0.44, p = 0.01). High-grade CSO EPVS positively correlated with BBB leakage (r = 0.58, p < 0.001). The BBB permeability of CSO negatively correlated with verbal fluency (r = −0.52, p < 0.001) and attention (r = −0.40, p = 0.01). Conclusions: High-grade CSO EPVS is related to BBB leakage, which contributes to cognitive impairment in AD patients, especially verbal frequency. CSO EPVS can function as a convenient AD marker for intervention and therapy.
Katherine Araya#, Riley Watson#, Kamil Khanipov, George Golovko, Giulio Taglialatela #These authors contributed equally to this work.
Increased risk of dementia associated with herpes simplex virus infections: Evidence from a retrospective cohort study using U.S. electronic health records
Abstract: Background: Alzheimer's disease is the most common age-related dementia. Recent compelling evidence from previous retrospective electronic health record (EHRs) studies suggests that herpes simplex virus (HSV) infections may be a risk factor for developing dementia. However, no age and propensity score matched studies have been published in a United States general population cohort study to date. Objective: We aimed to identify whether HSV infection shows a significantly increased risk of the development of dementia in a sizable and heterogeneous cohort. We investigated whether herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), or coinfections with both serotypes pose a greater risk of developing dementia across different biological sexes and racial groups. Methods: EHRs from patients with a history of HSV or specific serotypes (HSV1 or HSV2) infection were selected for analysis. These records were compared to a propensity-matched control group and analyzed for hazard and odds ratios through TriNetX. Results: There was a significant difference in dementia incidence in the HSV-infected group versus the control. Individuals with a history of HSV, HSV1, HSV2, and coinfection all showed a significant risk of developing dementia compared to controls. Males with HSV2 are at a higher risk of dementia outcome than females with HSV2. Conclusions: While consistent with previous reports, these findings are the first to establish a higher risk of developing dementia in patients who have any HSV diagnosis using a nationwide, population-based matched cohort study in the United States.
Olena Iakunchykova, Henrik Schirmer, James M Roe, Øystein Sørensen, Tom Wilsgaard, Laila A Hopstock, Anne Elise Eggen, Michael E Benros, Chi-Hua Chen, Yunpeng Wang
Longitudinal and concurrent C-reactive protein and diet associations with cognitive function in the population-based Tromsø Study
Abstract: Background: Immune dysregulation has been implicated in Alzheimer’s disease; however, precise mechanisms and timing have not been established. Objective: To investigate the concurrent and longitudinal associations of serum C-reactive protein (CRP) and dietary inflammatory index (DII) with cognitive decline as observed in Alzheimer’s disease. Methods: The study was based on 7613 individuals who participated in Tromsø6 (2007-2008) and Tromsø7 (2015-2016). We analyzed the relationship between CRP levels, DII, and cognitive function cross-sectionally using linear regression. We used mediation analysis to examine if CRP mediates the effects of DII on cognitive function. Further, we related baseline serum CRP to cognitive function and to change in cognitive function after 7 years of follow up. We used linear mixed models to relate changes in CRP levels to changes in cognitive function measured at two time points with 7 years apart. Results: Both CRP level and DII were cross-sectionally inversely associated with cognitive function (psychomotor speed, executive function). There was no prospective relationship between CRP level at baseline and cognitive function after 7 years of follow up. Increase in CRP levels was associated with decrease in cognitive function (psychomotor speed, executive function, and verbal memory) observed between two measurements 7 years apart. The mediation model did not show convincing evidence of a mediating effect of CRP in the association between diet and cognitive function. Conclusions: After comprehensive analysis of associations between CRP, DII and cognitive function, we conclude that CRP is likely to reflect the changes in inflammatory environment occurring in parallel with cognitive decline.
Kristina Randlová, Peter Pažitný, Daniela Kandilaki
Institutionalization of persons with Alzheimer’s disease in the Czech and Slovak Republics
Abstract: Background: The prevalence of Alzheimer's disease (AD) is increasing, and with it comes the demand for specialized services. Current information on the institutionalization of patients with AD is limited. Objective: To determine the level of institutionalization among AD patients in the facilities of the Czech Republic and the Slovak Republic. Methods: A survey of the rate of institutionalization in facilities in the Czech Republic and Slovak Republic. The survey collects data on the institutionalization of patients suffering from AD in relation to the capacity of the facilities and the prevalence of the disease. Data were collected by representative quantitative survey, during years 2019–2021. Results: Patients with AD occupy approximately 25% of the total capacities of institutions in the Czech and Slovak Republics. The rate of institutionalization of patients with AD is estimated at 20.5% in the Czech Republic and 24% in the Slovak Republic. This is more than the estimated worldwide rate of institutionalization of people with AD (16%) but less than the estimated rate of institutionalization of these patients in high-income countries (31%). Conclusions: As the prevalence of AD increases, so do the demands for care. If there is no increase in institutional capacity, this growth will put more pressure on home care. In order to provide specialized care to as many patients as possible, emphasis must be placed on increasing the capacity of institutions.
Olga Netsyk, Sergiy V Korol, Jin-Ping Li, Bryndis Birnir#, Zhe Jin# #These authors contributed equally to this work.
GABA-activated slow spontaneous inhibitory postsynaptic currents are decreased in dorsal hippocampal dentate gyrus granule cells in an aged mouse model of Alzheimer’s disease
Abstract: Background: Synaptic transmission dysfunction is associated with a range of neurological disorders, including Alzheimer’s disease (AD). However, the role of γ-aminobutyric acid (GABA)-mediated synaptic inhibition in AD has not been fully explored. Objective: We studied basal, GABA-activated slow spontaneous synaptic currents (sIPSCs) in dentate gyrus (DG) granule cells in the dorsal hippocampus of an AD mouse model (tg-APPSwe) and investigated insulin’s modulatory effects. Methods: GABA-activated slow sIPSCs were recorded in the DG granule cells by whole-cell patch¬-clamp recordings in dorsal hippocampal brain slices from 5-6 (adult) and 10-12 (aged) months old wild-type (WT) and AD mice, in the presence or absence of insulin (1 nM). Results: The median 10-90% rise time of slow sIPSCs significantly decreased with age (10-12 months vs. 5-6 months) only in AD mice. The median amplitude of the slow sIPSCs was decreased in adult and aged AD mice as compared to WT mice whereas the slow sIPSCs frequency was only reduced in the aged WT mice. The median 63% decay time and total current density of the slow IPSCs was significantly decreased in the aged AD mice as compared to both WT mice and to the adult AD mice. Insulin application exerted no effect on slow sIPSCs properties in any of the animal groups. Conclusions: The characteristics of the slow sIPSCs recorded in DG granule cells of dorsal hippocampus from WT and AD mice are altered by age- and disease-state, whereas insulin has negligible effects.
Zu-Qi Chen, Meng-Ting Wang, Cheng-Rong Tan, Shan Huang, Fa-Ying Zhou, Ying-Ying Shen, Gui-Hua Zeng, Dong-Yu Fan, Yan-Jiang Wang (Handling Associate Editor: Peng Lei)
Clinical relevance of plasma ADAM-17 with cognition and neurodegeneration in Alzheimer’s disease
Abstract: Background: A disintegrin and metalloproteinase 17 (ADAM-17) has multiple pathophysiological functions in Alzheimer’s disease (AD). However, the clinical relevance of ADAM-17 in AD is not clear yet. Objective: This study aims to investigate the levels of circulating ADAM-17 and their association with AD. Methods: This cross-sectional study recruited 40 normal cognition (NC) participants and 36 AD patients. Plasma ADAM-17 and biomarkers of neurodegeneration were determined. The association of plasma ADAM-17 with cognitive functions and biomarkers of neurodegeneration was analyzed. Results: Plasma ADAM-17 levels were elevated in AD patients in comparison with NC subjects. Plasma ADAM-17 was positively associated with Clinical Dementia Rating (CDR) scores, but negatively associated with the Mini-Mental State Examination scores and Montreal Cognitive Assessment scores. Plasma ADAM-17 levels were positively associated with the levels of Aβ40, Aβ42, and p-Tau181. Conclusions: These findings suggest a link between ADAM-17 and the pathogenesis of AD from a clinical perspective.
Jonathan Adrián Zegarra-Valdivia, Tal Shany-Ur, Myrthe Gwen Rijpma, Patrick Callahan, Pardis Poorzand, Scott Grossman, Bailey McEachen, Joel H Kramer, Bruce L Miller, Katherine P Rankin
Validation of the Cognitive-Emotional Perspective Taking (CEPT) test in patients with neurodegeneration
Abstract: Background: Theory of mind (ToM) is crucial for socioemotional interaction. ToM deficits may explain behavioral changes in dementia, especially Alzheimer's disease (AD) and frontotemporal dementia (FTD). Objective: This study examined the psychometrics of a new ToM test in healthy adults, identified ToM differences in dementia syndromes, and assessed if ToM scores predict neuropsychiatric function and real-life behavior. Methods: The UCSF Cognitive and Emotional Perspective Taking Test (CEPT) was evaluated in 195 healthy adults (age: 42.69 ± 16.20) and in a clinic cohort of 304 participants (age: 64.07 ± 9.2). Participants included healthy controls, AD, behavioral-variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent PPA (nfvPPA), and progressive supranuclear palsy (PSP) patients. CEPT’s psychometrics were assessed, and ToM differences and predictions of neuropsychiatric symptoms were analyzed using regression models. Results: In controls, CEPT showed good validity and reliability. In patients, CEPT scores correlated with executive and emotional measures, but not language measures, showing good construct validity. Cognitive ToM was most impaired in AD and bvFTD, with less impairment in svPPA and PSP, and all patient groups showed impaired emotional ToM. ToM performance predicted real-life neuropsychiatric behavior, including anxiety, apathy, disinhibition, and aberrant motor behaviors. Conclusions: ToM deficits appear early in dementia syndromes and predict neuropsychiatric behavior. Assessing ToM and social cognition with ecologically valid tasks may help identify altered social cognition in early neurodegeneration.
Fabrizia D’Antonio, Giorgio Vivacqua, Marco Serrentino, Martyna Podgajna, Aleksandra Skweres, Martina Peconi, Maria Ilenia De Bartolo, Massimiliano Panigutti, Micaela Sepe Monti, Giuseppina Talarico, Giovanni Fabbrini, Giuseppe Bruno (Handling Associate Editor: Carla Abdelnour)
Salivary biomarkers for the molecular diagnosis of dementia with Lewy bodies
Abstract: Background: Despite dementia with Lewy bodies (DLB) being the second most common form of neurodegenerative dementia, there are no available biofluid biomarkers for diagnosis. Alpha-synuclein (a-syn) and tau species have been detected in biological fluids of DLB patients and saliva represents an easily accessible and non-invasive source for biomarker detection. Objective: We aimed to investigate salivary a-syn and tau species assessing their potential in the diagnosis of DLB. Methods: We measured total and oligomeric a-syn, total-tau, and S199-phosphorylated-tau (pS199-tau) in the saliva of 21 DLB, 20 Alzheimer’s disease (AD), 20 Parkinson’s disease (PD) patients, and 20 healthy subjects (HS) using quantitative enzyme-linked immunosorbent assay (ELISA) analyses. Results: All pathological groups had higher oligomeric a-syn concentration than HS. Salivary total-tau concentration was higher in all the pathological groups than HS, whereas the concentrations did not differ among patients’ groups. Conversely, salivary pS199-tau was higher in DLB and AD patients than in HS and PD patients. Both correlation matrix and principal component analysis showed that core clinical DLB features were related to a-syn pathology, while cognitive decline was associated with salivary levels of pS199-tau in both DLB and AD patients. Receiver operating characteristic analysis reported high diagnostic accuracy for both a-syn oligomers and pS199-tau, between DLB and HS, and an adequate accuracy between DLB and PD. Conclusions: These findings provide preliminary evidence that salivary a-syn and tau species might be promising in identifying DLB patients on respect to PD patients and HS, while the diagnostic potential is limited on respect to AD.
Xiang Gao, Zuoli Sun, Jia Hu, Yuhong Li, Qi Deng, Rena Li
Identification of the enzymatic cleavage relationship between anti-aging protein α-Klotho and Alzheimer’s disease biomarker BACE1
Abstract: Background: The α-Klotho is known to be involved in longevity and various age-related diseases, including cognitive impairment. BACE1, an important enzyme associated with the pathological process of Alzheimer's disease (AD), serves as a biomarker for predicting changes in cognitive function. Although both proteins are closely linked to age-related cognitive function, the mechanism of their interaction remains unclear. Objective: To identify the enzymatic digestion relation between α-Klotho and BACE1 and the specific cleavage site. Methods: Thirty elderly and forty-five young individuals were recruited. The cleavage product was identified by Coomassie blue staining, western blot, and MALDI-TOF mass spectrometry. The concentrations of plasma proteins were measured by ELISA. Results: A new protein product was identified after the digestion reaction. BACE1 cleaved the α-Klotho peptide 951-981 at the F-T residues. When the F-T residues were replaced with K-K, BACE1 was unable to cleave the mutant peptide. The plasma levels of α-Klotho were significantly lower in elderly participants than in young participants (p < 0.0001). However, there was no significant difference in plasma BACE1 levels between elderly and young participants (p = 0.164). In elderly adults, there was a significant positive correlation between plasma BACE1 and α-Klotho protein levels (p = 0.009, r = 0.469), while this correlation was not observed in young adults (p = 0.170, r = -0.208). Conclusions: The anti-aging protein α-Klotho is a substrate of BACE1 with a specific cleavage site at F-T. The BACE1/α-Klotho pathway may serve as a common axis for age-related cognitive decline.
Joshua L Milstein, Joshua A Kulas, Aria Kamal, An B Lo, Heather A Ferris
Regulation of glial ApoE secretion by the mevalonate pathway is independent of ApoE isoform
Abstract: Background: Lipids synthesized in astrocytes are distributed to other brain cells in high-density lipoprotein-like ApoE particles. ApoE, which is a powerful genetic risk factor for developing Alzheimer’s disease, is secreted differently depending on genotype. Secretion of ApoE from mouse astrocytes is regulated by the mevalonate pathway. Objective: We aimed to understand if the regulation of ApoE secretion from astrocytes by the mevalonate pathway was the same between mouse ApoE and ApoE from humanized mice, and if this is impacted by ApoE isoform. Methods: Astrocyte-enriched glial cultures from wild-type and humanized ApoE targeted-replacement mice were treated with pharmacological inhibitors of various steps along the mevalonate pathway and ApoE in the conditioned media was measured. Results: We show that statins and prenylation inhibitors, but not specific cholesterol inhibitors, reduce extracellular ApoE lipoparticle levels in astrocyte-enriched glial cultures, and that this occurs in cells harboring either the mouse ApoE or any of the three human ApoE genotypes to a similar extent. We find that geranylgeranylation modulates ApoE release from astrocytes, and it does so independent of ApoE genotype. Conclusions: Our results suggest that prenylation broadly regulates ApoE secretion from astrocytes regardless of ApoE genotype, and that this is mediated specifically by geranylgeranylation. Therefore, our data implicates geranylgeranylation as a general mechanism modulating ApoE release from astrocytes, but likely is not responsible for the reported baseline differences in ApoE secretion seen in vivo and in vitro across genotypes.
Samah H Hajjar, Saad M Alsaad, Maram A AlFouzan, Shaimaa N Rohaiem, Sultan H Alamri, Tahani N Altamimi, Abdulaziz A Alodhayani, Hany I Hassanin, Khalid S AlHarkan, Afaf A Albalawi, Nuzayhah A Almuzaen, Jamaan M Alzahrani, Assim M AlAbdulKader, Muna A Almaghaslah, Abdullah I Alsuhail, Raneem G Milyani, Eman N Almashjary, Hashim H Balubaid, Louay H Al Khamis, Abdulmohsen H Al-Zalabani , Ahmed S Mohammedin
Dementia prevalence within the Kingdom of Saudi Arabia National Guard Health System (2015-2023): An exploratory epidemiological study
Abstract: Background: Dementia is recognized as one of the prevalent neurocognitive disorders among older adults in Saudi Arabia, yet research efforts on its prevalence remains limited and fragmented, making it difficult to gain a full understanding of its epidemiology. Objective: To explore dementia epidemiology and associated data within the older population in the sector of National Guard Health System (NGHS), Saudi Arabia. Methods: This was a multicenter study that utilized medical records from NGHS centers across the country. We included data from all individuals aged 50 years and older who sought medical care between January 1, 2015, and January 1, 2023. Results: Nearly half of the study's participants were men (51.9%), with the majority being diagnosed between the ages of 70-79 years (38.5%) and 80-89 years (31%). Dementia was identified in 3.37% of participants. The most prevalent subtype was late-onset Alzheimer’s disease (35.6%), followed by unspecified dementia (18.4%). Significant differences between genders were observed, particularly in the age at diagnosis (p = 0.003) and the prevalence of ischemic strokes as a risk factor (p < 0.001). Conclusions: In this multicenter study utilizing the NGHS cohort, Alzheimer's disease emerged as the most prevalent subtype of dementia. Early symptoms of delirium, depression, and sleep disturbances are key indicators for the early detection of dementia. This research has the potential to influence clinical practices by enhancing the early identification and management of dementia and provides a solid foundation for developing evidence-based policy strategies to tackle the increasing challenges of dementia in Saudi Arabia.
Jian Yang#, Huitong Ding#, Yi Li, Ting Fang Alvin Ang, Sherral Devine, Yulin Liu, Wendy Qiu, Rhoda Au, Jiantao Ma, Chunyu Liu #These authors contribute equally to this work.
Association of mid-age Life’s Essential 8 score with digital cognitive performance and incident Alzheimer’s disease: The Framingham Heart Study
Abstract: Background: Cardiovascular health (CVH) is a modifiable risk factor for Alzheimer’s disease (AD). However, studies examining the association between mid-life CVH, as indicated by Life’s Essential 8 (LE8) health metrics, and digital cognitive performance or AD risk are limited. Objective: To examine the associations between mid-age CVH, assessed by LE8 scores during ages 45 to 65, and digital clock drawing test (dCDT) performance as well as the incidence of AD. Methods: We included 1,198 participants (51.6% women) from the Framingham Heart Study (FHS) Offspring cohort. Linear regression and Cox proportional hazards models were applied to examine the associations between mid-age CVH and dCDT performance, as well as the incidence of AD. Results: Over a median follow-up of 17.5 years, 45 participants developed AD. Each standard deviation higher mid-age LE8 total score was associated with a 0.16 standard deviation higher level of the dCDT total score (p<0.001) and a 0.35-fold lower risk of incident AD (HR=0.65, 95% CI: 0.49–0.87, p=0.003). The dCDT measures showed stronger associations with mid-age LE8 and AD risk compared to the conventional CDT (cCDT). For example, the drawing score on copy tasks was more strongly associated with LE8 (beta=0.10, p=0.007 versus beta=0.08, p=0.27) and had higher discrimination for incident AD (C-stat=0.89 versus 0.83) compared to the cCDT. Conclusions: Our results highlight the potential of digital cognitive assessments for evaluating AD risk and emphasize the importance of mid-age CVH in shaping cognitive outcomes and the development of AD.
Patrycja Dzianok, Jakub Wojciechowski, Tomasz Wolak, Ewa Kublik (Handling Associate Editor: Rose Bruffaerts)
Alzheimer's disease-like features in resting state EEG/fMRI of cognitively intact and healthy middle-aged APOE/PICALM risk carriers
Abstract: Background: Genetic susceptibility is a primary factor contributing to etiology of late-onset Alzheimer's disease (LOAD). The exact mechanisms and timeline through which APOE/PICALM influence brain functions and contribute to LOAD remain unidentified. This includes their effects on individuals prior to the development of the disease. Objective: To investigate the effects of APOE and PICALM risk genes on brain health and function in non-demented individuals. This study aims to differentiate the combined risk effects of both genes from the risk associated solely with APOE, and to examine how PICALM alleles influence the risk linked to APOE. Methods: APOE/PICALM alleles were assessed to determine the genetic risk of LOAD in 79 healthy, middle-aged participants who underwent electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings. The resting-state signal was analyzed to estimate relative spectral power, complexity (Higuchi's algorithm), and connectivity (coherence in EEG and independent component analysis-based connectivity in fMRI). Results: The main findings indicated that individuals at risk for LOAD exhibited reduced signal complexity and the so-called “slowing of EEG” which are well-known EEG markers of Alzheimer’s disease. Additionally, these individuals showed altered functional connectivity in fMRI (within attention-related areas). Conclusions: Risk alleles of APOE/PICALM may affect brain integrity and function prior to the clinical onset of the disease.
Heather D Gibbs, Matthew K Taylor, Cheryl Gibson, Rebecca R Mount, Austin Sullivan, Kristine Williams, Debra K Sullivan
Uncovering nutrition needs in dyads of caregivers and persons with dementia
Abstract: Background: Nutrition risk is common in Alzheimer’s disease and is associated with symptoms of dementia, cognitive decline, institutionalization, and mortality. Family caregivers who increasingly manage nutrition needs of persons with dementia (PWD) experience high caregiver burden, low health literacy, and nutrition risk. Few interventions for informal caregivers have included nutrition. Objective: To inform design of a future caregiver nutrition intervention. Methods: This cross-sectional study used a convergent mixed methods approach to 1) assess nutrition status among PWD and caregiver dyads (measures in common included Mini Nutrition Assessment, skin carotenoid, and handgrip strength), and 2) interview caregivers to identify needs and barriers for nutrition intervention. We hypothesized caregiver nutrition literacy is associated with PWD nutrition risk. Data collected in nutrition assessment and interviews were analyzed separately then side-by-side for comparison. Results: Of 50 dyads, 48% had at least one individual exhibiting nutrition risk, and nutrition status categories (χ2=6.25, p=0.012) between caregivers and PWD were related. Caregiver nutrition literacy was associated with 1) PWD factors including nutrition risk (rho=0.244), body mass index (BMI) (rho=0.421), handgrip strength (rho=0.283), and skin carotenoid (rho=0.351), and 2) Caregiver factors including nutrition risk (rho=0.304), diet quality (rho=0.304), and BMI (rho=0.333). Interviews with 18 caregivers found caregivers prioritize PWD nutrition, provide more PWD nutrition care since diagnosis, experience social isolation, and would attend nutrition interventions if PWD are included. Conclusions: Nutrition risk was more common among caregivers when PWD demonstrated nutrition risk. Factors present in individuals within the dyad were associated with partner nutrition risk. Future research should identify effective approaches for intervening on dyadic nutrition risk.
Jiayi Ding, Meina Quan, Peixi Zang, Jianping Jia
Associations between serum metabolic syndrome indicators levels and cerebrospinal fluid pathological protein in dementia and pre-dementia patients
Abstract: Background: Metabolic syndrome (MetS) was associated with an increased incidence of mild cognitive impairment (MCI) and progression to dementia. Objective: To study the associations between MetS indicators and cerebrospinal fluid (CSF) biomarkers in the participants. Methods: 61 normal cognition, 66 mild MCI, and 135 dementia participants were included in our study, with the results of lumbar puncture and peripheral blood biochemistry. The CSF levels of amyloid-β (Aβ)42 protein, total tau protein, phosphorylated tau protein, and Aβ42/40 ratio, were selected as the biomarkers. The body mass index, the plasma high density lipoprotein cholesterol, uric acid, low density lipoprotein cholesterol, triglyceride, and homocysteine levels were selected as indicators of MetS. Linear regression model was used to analyze the correlation in all participants and different cognitive stages, controlling for age, gender, and APOE genotype. Results: Our study showed that MetS indicators were associated with CSF biomarkers in participants after adjusting for possible confounding factors, including age, gender, and APOE genotype. The results of our grouping analysis further supported the potential association between plasma MetS indicators and CSF biomarkers in three group. We found that the dementia group showed the greatest correlation coefficient. Conclusions: The CSF pathological proteins concentrations were associated with MetS indicators, and the correlation coefficient were greater in the dementia stage. These findings suggest that regulating peripheral metabolism may affect the level of pathological proteins in the brain to improve cognitive impairment.
Shun Zhu#, Jingnian Ni#, Siwei Long, Yuou Teng, Yirou Yao, Jing Shi, Jinzhou Tian #These authors contributed equally to this work.
Androgen deprivation therapy and dementia risk: An updated and dose-response meta-analysis
Abstract: Background: The association between androgen deprivation therapy (ADT) and dementia risk is controversial, and the dose-response relationship between them remains unclear. Objective: We aim to further clarify the relationship between ADT and dementia risk. Methods: PubMed, Web of Science, Embase, and Cochrane Library databases were systematically searched up to September 2024 to identify relevant studies. A meta-analysis was conducted using hazard ratios (HR) and 95% confidence intervals (CI) as pooled indicators. The robust error meta-regression (REMR) approach was performed to explore the dose-response relationship. Heterogeneity was assessed using I² statistics, and subgroup analysis, sensitivity analysis, and meta-regressions were conducted. Publication bias was evaluated with a funnel plot and Egger's test. Results: Our meta-analysis of 21 studies involving 2,278,835 patients revealed that ADT significantly increased the risk of overall dementia (HR = 1.14, 95% CI: 1.06-1.20) and Alzheimer's disease (AD) (HR = 1.15, 95% CI: 1.06-1.23), but not non-AD dementia (HR = 1.01, 95% CI: 0.89-1.16). For ADT subtypes, anti-androgens increased the risk of overall dementia (HR = 1.27, 95% CI: 1.09-1.49), particularly for AD (HR = 1.53, 95% CI: 1.19-1.97), while Luteinizing hormone-releasing hormone therapy and bilateral orchiectomy were not linked to the risk of any dementia subtype. A bell-shaped non-linear relationship between ADT duration and dementia risk was observed, with the highest risk observed at 15.5 to 21.5 months (HR = 1.25), which was confirmed by subgroup analysis for AD. Conclusions: The risk of overall dementia and AD were found to be significantly associated with ADT in a bell-shaped dose-response effect.
Edoardo Nicolò Aiello, Beatrice Curti, Giulia De Luca, Marta Trombi, Alessio Maranzano, Barbara Poletti, Vincenzo Silani, Nicola Ticozzi, Federico Verde (Handling Associate Editor: Carlo Abbate)
Prevalence and correlates of the head turning sign in mild cognitive impairment and dementia due to neurodegenerative, chronic cerebrovascular, and mixed etiologies
Abstract: Background: The head turning sign (HTS) consists in the patient turning his/her head towards the accompanying person in search for support when being asked questions. Although the HTS is known to be associated with cognitive impairment, previous investigations were biased towards Alzheimer’s disease (AD) or did not differentiate between diverse dementia etiologies; moreover, little is known about the specific cognitive correlates of the HTS. Objective: To assess the prevalence and clinical correlates of the HTS in patients with mild cognitive impairment (MCI) and dementia of various etiologies. Methods: The HTS was recorded during the Mini-Mental State Examination (MMSE) in 232 MCI/dementia patients with the following etiological classification: AD (N=121); frontotemporal lobar degeneration (FTLD; N=24); Lewy body disease (LBD; N=11); vascular (N=29); mixed (N=47). Results: The overall prevalence of the HTS in the whole cohort was 27.6%. Albeit being descriptively higher in dementia (29.9%) versus MCI (22.7%), as well as descriptively lower in FTLD and LBD than in remaining subgroups, no significant association was detected between the HTS and either MCI/dementia status or etiology. HTS+ patients were older and more frequently females, also reporting lower MMSE scores and differing from HTS- ones on Temporal and Spatial Orientation and Constructional Praxis sub-scores. An association between the HTS and lower MMSE scores was found in patients with MCI but not in those with dementia. Conclusions: In patients with cognitive impairment due to diverse causes, the HTS might occur regardless of MCI versus dementia status and across different etiologies. MCI patients displaying the HTS might have more severe cognitive deficits.
Qi Li, Jian-meng Huo, Cun-xian Jia, Fei-fei Jia
Relationship between development trajectories of leisure activity and sleep time on incident cognitive impairment: A study based on the Chinese Longitudinal Healthy Longevity Survey (CLHLS)
Abstract: Background: Leisure activity and sleep time are key factors in cognitive impairment, but the impact of their long-term trajectories on incident cognitive impairment remains unclear. Objective: To examine the association of leisure activity trajectories, sleep time trajectories and their combined effects with incident cognitive impairment in older adults. Methods: Data from the Chinese Longitudinal Healthy Longevity Survey (2008-2018) were analyzed, including adults aged ≥65 who participated in at least three surveys. Group-based trajectory modeling explored leisure activity and sleep time patterns. Cox proportional-hazards regression model assessed the association of leisure activity trajectories and sleep time trajectories and their combined effects with incident cognitive impairment. Results: We included 3094 participants with a median follow-up of 6.07 years. The optimal trajectory groups for leisure activity and sleep time were four and three, respectively. The low-level leisure activity group were associated with an increased risk of cognitive impairment (HR, 95%CI: 2.07, 1.37-3.13), whereas the high-level leisure activity group were associated with a reduced risk of cognitive impairment (HR, 95%CI: 0.60, 0.36-0.99). Short sleep time group was associated with a reduced risk of cognitive impairment (HR, 95%CI: 0.62, 0.41-0.92). In the combined effect, leisure activity belonging to the low-level group and sleep time belonging to the moderate sleep time group or the long sleep time group were associated with an increased risk of cognitive impairment. Conclusions: Long-term high-level leisure activity and short sleep time are associated with a reduced risk of cognitive impairment in older adults.
Natasa Popovic, Noemi Lois, Santiago Pérez-Hoyos, Rafael Simó, Lieza G Exalto on behalf of the RECOGNISED consortium
Revisiting the Montreal Cognitive Assessment in a European cohort of elderly living with type 2 diabetes
Abstract: Background: Individuals with type 2 diabetes have an increased risk of developing both vascular dementia and Alzheimer’s disease. Objective: This prospective cross-sectional study assessed the screening ability of the standard Montreal Cognitive Assessment (MoCA) score suggestive of mild cognitive impairment (<26) in a European cohort of individuals ≥65 of age with type 2 diabetes. Methods: Participants of RECOGNISED, a European prospective EU-funded cohort study, were screened using MoCA. In addition, a 13-item Neuropsychological Test Battery (NTB) with the Clinical Dementia Rating was undertaken to categorize participants as normocognitive (NC, n=128) or mild cognitive impaired (MCI, n=185). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of MoCA cut-off scores to categorize patients as having MCI or not. Results: The standard MoCA cut-off of 25/26 demonstrated a sensitivity of 88% and a specificity of 51%, resulting in a false positive rate of 20%. ROC analysis showed that a MoCA cut-off of 24/25 has a better balance between sensitivity (81%) and specificity (62%), with a lower false positive rate of 16%. NTB results showed that the MCI group had the lowest norm-referenced percentile scores in the visuo-construction domain, a known early feature of Alzheimer’s disease and a significant predictor of a rapid rate of disease progression. Conclusions: MoCA as a screening tool in individuals ≥65 with type 2 diabetes, overestimates the prevalence of MCI, even when applying lower cut-offs. More specific screening strategies are necessary, particularly targeting the visuo-construction domain, to effectively identify cognitive impairment in individuals with type 2 diabetes.
