Topographical Information-Based High-Order Functional Connectivity and Its Application in Abnormality Detection for Mild Cognitive Impairment. - Zhang, Han; Chen, Xiaobo; Shi, Feng; Li, Gang; Kim, Minjeong; Giannakopoulos, Panteleimon; Haller, Sven; Shen, Dinggang (J Alzheimers Dis, 2016)
Temporal synchronization-based functional connectivity (FC) has long been used by the neuroscience community. However, topographical FC information may provide additional information to characterize the advanced relationship between two brain regions. Accordingly, we proposed a novel method, namely high-order functional connectivity (HOFC), to capture this second-level relationship using inter-regional resemblance of the FC topographical profiles. Specifically, HOFC first calculates an FC profile for each brain region, notably between the given brain region and other brain regions. Based on these FC profiles, a second layer of correlations is computed between all pairs of brain regions (i.e., correlation's correlation). On this basis, we generated an HOFC network, where "high-order" network properties were computed. We found that HOFC was discordant with the traditional FC in several links, indicating additional information being revealed by the new metrics. We applied HOFC to identify biomarkers for early detection of Alzheimer's disease by comparing 77 mild cognitive impairment patients with 89 healthy individuals (control group). Sensitivity in detection of group difference was consistently improved by ∼25% using HOFC compared to using FC. An HOFC network analysis also provided complementary information to an FC network analysis. For example, HOFC between olfactory and orbitofrontal cortices was found significantly reduced in patients, besides extensive alterations in HOFC network properties. In conclusion, our results showed promise in using HOFC to comprehensively map the human brain connectome.

Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration. - Iyappan, Anandhi; Gündel, Michaela; Shahid, Mohammad; Wang, Jiali; Li, Hui; Mevissen, Heinz-Theodor; Müller, Bernd; Fluck, Juliane; Jirsa, Viktor; Domide, Lia; Younesi, Erfan; Hofmann-Apitius, Martin (J Alzheimers Dis, 2016)
Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.

Tract-Specific Correlates of Neuropsychological Deficits in Patients with Subcortical Vascular Cognitive Impairment. - Jung, Na-Yeon; Han, Cheol E; Kim, Hee Jin; Yoo, Sang Wook; Kim, Hee-Jong; Kim, Eun-Joo; Na, Duk L; Lockhart, Samuel N; Jagust, William J; Seong, Joon-Kyung; Seo, Sang Won (J Alzheimers Dis, 2016)
The white matter tract-specific correlates of neuropsychological deficits are not fully established in patients with subcortical vascular cognitive impairment (SVCI), where white matter tract damage may be a critical factor in cognitive impairment. The purpose of this study is to investigate the tract-specific correlates of neuropsychological deficits in SVCI patients using tract-specific statistical analysis (TSSA). We prospectively recruited 114 SVCI patients, and 55 age-, gender-, and education-matched individuals with normal cognition (NC). All participants underwent diffusion weighted imaging and neuropsychological testing. We classified tractography results into fourteen major fiber tracts and analyzed group comparison and correlation with cognitive impairments. Relative to NC subjects, SVCI patients showed decreased fractional anisotropy values in bilateral anterior-thalamic radiation, cingulum, superior-longitudinal fasciculus, uncinate fasciculus, corticospinal tract, and left inferior-longitudinal fasciculus. Focal disruptions in specific tracts were associated with specific cognitive impairments. Our findings suggest that disconnection of specific white matter tracts, especially those neighboring and providing connections between gray matter regions important to certain cognitive functions, may contribute to specific cognitive impairments in SVCI.
Keywords: Aged; Brain; Cerebrovascular Disorders; Cognitive Dysfunction; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Female; Gray Matter; Humans; Male; Neural Pathways; Neuropsychological Tests; White Matter

Transcriptional Analysis of Blood Lymphocytes and Skin Fibroblasts, Keratinocytes, and Endothelial Cells as a Potential Biomarker for Alzheimer's Disease. - Mukhamedyarov, Marat A; Rizvanov, Albert A; Yakupov, Eduard Z; Zefirov, Andrey L; Kiyasov, Andrey P; Reis, Helton J; Teixeira, Antônio L; Vieira, Luciene B; Lima, Luciana M; Salafutdinov, Ilnur I; Petukhova, Elena O; Khaiboullina, Svetlana F; et al. (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a devastating and progressive form of dementia that is typically associated with a build-up of amyloid-β plaques and hyperphosphorylated and misfolded tau protein in the brain. Presently, there is no single test that confirms AD; therefore, a definitive diagnosis is only made after a comprehensive medical evaluation, which includes medical history, cognitive tests, and a neurological examination and/or brain imaging. Additionally, the protracted prodromal phase of the disease makes selection of control subjects for clinical trials challenging. In this study we have utilized a gene-expression array to screen blood and skin punch biopsy (fibroblasts, keratinocytes, and endothelial cells) for transcriptional differences that may lead to a greater understanding of AD as well as identify potential biomarkers. Our analysis identified 129 differentially expressed genes from blood of dementia cases when compared to healthy individuals, and four differentially expressed punch biopsy genes between AD subjects and controls. Additionally, we identified a set of genes in both tissue compartments that showed transcriptional variation in AD but were largely stable in controls. The translational products of these variable genes are involved in the maintenance of the Golgi structure, regulation of lipid metabolism, DNA repair, and chromatin remodeling. Our analysis potentially identifies specific genes in both tissue compartments that may ultimately lead to useful biomarkers and may provide new insight into the pathophysiology of AD.

Transferring cut-off values between assays for cerebrospinal fluid Alzheimer's disease biomarkers. - García Barrado, Leandro; Coart, Els; Vanderstichele, Hugo M J; Burzykowski, Tomasz (J Alzheimers Dis, 2016)
Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab- and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Bayes Theorem; Biomarkers; Cognitive Dysfunction; Datasets as Topic; Humans; Linear Models; Multivariate Analysis; Peptide Fragments; tau Proteins

Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor. - Li, Xinyi; Song, Yuanli; Sanders, Charles R; Buxbaum, Joel N (J Alzheimers Dis, 2016)
In Alzheimer's disease (AD), most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed overexpression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study, in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP, with Kd = 86±9 μM. In cultured cells expressing both proteins, the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase, significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1, these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis.

Two Phase 2 Multiple Ascending-Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer's Disease. - Pasquier, Florence; Sadowsky, Carl; Holstein, Ann; Leterme, Ghislaine Le Prince; Peng, Yahong; Jackson, Nicholas; Fox, Nick C; Ketter, Nzeera; Liu, Enchi; Ryan, J Michael (J Alzheimers Dis, 2016)
Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx-40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16-56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.
Keywords: Adjuvants, Immunologic; Aged; Alzheimer Disease; Amyloid beta-Peptides; Antipsychotic Agents; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Interferon-gamma; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Recombinant Fusion Proteins; Saponins; Single-Blind Method; Treatment Outcome

UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. - Xie, Min; Han, Yun; Yu, Quntao; Wang, Xia; Wang, Shaohui; Liao, Xiaomei (J Alzheimers Dis, 2016)
Ubiquitin C-terminal hydrolase L1 (UCH-L1) is critical for protein degradation and free ubiquitin recycling. In Alzheimer's disease brains, UCH-L1 is negatively related to neurofibrillary tangles whose major component is hyperphosphorylated tau protein, but the direct action of UCH-L1 on tau has not been reported. In the current study, mouse neuroblastoma Neuro2a (N2a) cells were treated by the different concentrations of UCH-L1 inhibitor LDN (2.5, 5 and 10 μM) to inhibit the hydrolase activity of UCH-L1. In addition, we also used UCH-L1 siRNA to treat the HEK293/tau441 cells to decrease the expression of UCH-L1. After LDN and UCH-L1 siRNA treatment, we used immunofluorescence, immunoprecipitation, and tau-microtubule binding assay to measure the microtubule-binding ability and post-translational modifications of tau protein. All the results presented that both inhibition of the activity and expression of UCH-L1 induced the decreased microtubule-binding ability and increased phosphorylation of tau protein. Abnormal aggregation and ubiquitination of tau protein was also observed after UCH-L1 inhibition. The above results suggested that aggregation of tau protein might be devoted to the abnormal post-translational modifications of tau protein. Our study first indicates that dysfunction of UCH-L1 most likely affected normal biological function of tau protein through decreasing degradation of ubiquitinated and hyperphosphorylated tau.
Keywords: Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Immunoprecipitation; Indoles; Mice; Microtubules; Neuroblastoma; Oximes; Protein Binding; Proteolysis; RNA, Small Interfering; tau Proteins; Ubiquitin Thiolesterase; Ubiquitination

Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia. - Dermody, Nadene; Wong, Stephanie; Ahmed, Rebekah; Piguet, Olivier; Hodges, John R; Irish, Muireann (J Alzheimers Dis, 2016)
Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

Unmet Needs of Community-Dwelling Primary Care Patients with Dementia in Germany: Prevalence and Correlates. - Eichler, Tilly; Thyrian, Jochen René; Hertel, Johannes; Richter, Steffen; Wucherer, Diana; Michalowsky, Bernhard; Teipel, Stefan; Kilimann, Ingo; Dreier, Adina; Hoffmann, Wolfgang (J Alzheimers Dis, 2016)
BACKGROUND: To provide an optimal care for persons with dementia (PWD), their individual unmet needs have to be identified and comprehensively addressed. OBJECTIVES: Present analyses aim to describe the number and types of unmet needs of German primary care patients screened positive for dementia and factors associated with the number of unmet needs. METHODS: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, cluster-randomized controlled intervention trial. Analyses are based on the baseline data of 227 PWD (≥70 years, living at home) of the intervention group who had screened positive for dementia (DemTect<9) and received a standardized computer-assisted needs assessment. RESULTS: PWD had on average 8.77±5.04 unmet needs (Range = 0-31). More than 90% of the PWD had three or more unmet needs. Unmet needs were identified across all predefined 26 subcategories. The majority of unmet needs occurred in the domains "nursing treatment and care" (38%), "social counseling and legal support" (20%), and "pharmacological treatment and care" (15%). More impairment in the activities of daily living was the only factor that was significantly associated with a higher number of unmet needs, independent of age, gender, living situation, presence of an informal caregiver, cognitive impairment, and depression. CONCLUSIONS: Present results demonstrate that community-dwelling PWD had a broad range of varying unmet needs. These findings emphasize the importance of a comprehensive needs assessment that allows the identification of individual needs as the basis for a tailored intervention- such as Dementia Care Management- that can address these needs.
Keywords: Aged, 80 and over; Caregivers; Cross-Sectional Studies; Dementia; Depression; Female; Germany; Health Services Needs and Demand; Humans; Male; Needs Assessment; Prevalence

Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease1. - Schilling, Melissa A (J Alzheimers Dis, 2016)
Numerous studies have documented a strong association between diabetes and Alzheimer's disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amylose; Diabetes Mellitus; Humans; Insulin; Insulysin

Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment. - Ye, Byoung Seok; Jang, Eun Young; Kim, Seong Yoon; Kim, Eun-Joo; Park, Sun Ah; Lee, Yunhwan; Hong, Chang Hyung; Choi, Seong Hye; Yoon, Bora; Yoon, Soo Jin; Na, Hae Ri; Lee, Jae-Hong; et al. (J Alzheimers Dis, 2016)
BACKGROUND AND OBJECTIVE: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients. METHODS: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value. RESULTS: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD. CONCLUSIONS: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Body Mass Index; Body Weight; Cognitive Dysfunction; Dementia; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Male; Neuropsychological Tests; Registries

An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia. - Li, Wei; Huang, Edgar (J Alzheimers Dis, 2016)
With the rapidly expanding evidence on brain structural and functional changes in type 2 diabetes mellitus (T2DM) patients, there is an increasing need to update our understanding on how T2DM associates with dementia as well as the underlying pathophysiological mechanisms. A literature search of T2DM and dementia or cognition impairments was carried out in electronic databases Medline, EMBASE, and Google Scholar. In this review, the chosen evidence was limited to human subject studies only, and data on either type 1 diabetes mellitus (T1DM) or non-classified diabetes were excluded. T2DM is a risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), although AD pathological marker studies have not provided sufficient evidence. T2DM interacts additively or synergistically with many factors, including old age, hypertension, total cholesterol, and APOEɛ4 carrier status for impaired cognition functions seen in patients with T2DM. In addition, comorbid T2DM can worsen the clinical presentations of patients with either AD or VaD. In summary, T2DM increases the risk for AD through different mechanisms for VaD although some mechanisms may overlap. Tau-related neurofibrillary tangles instead of amyloid-β plaques are more likely to be the pathological biomarkers for T2DM-related dementia. Degeneration of neurons in the brain, impaired regional blood supply/metabolism, and genetic predisposition are all involved in T2DM-associated dementia or cognitive impairments.

Upregulation of Connexin 43 Expression Via C-Jun N-Terminal Kinase Signaling in Prion Disease. - Lee, Geon-Hwi; Jang, Byungki; Choi, Hong-Seok; Kim, Hee-Jun; Park, Jeong-Ho; Jeon, Yong-Chul; Carp, Richard I; Kim, Yong-Sun; Choi, Eun-Kyoung (J Alzheimers Dis, 2016)
Prion infection leads to neuronal cell death, glial cell activation, and the accumulation of misfolded prion proteins. However, the altered cellular environments in animals with prion diseases are poorly understood. In the central nervous system, cells connect the cytoplasm of adjacent cells via connexin (Cx)-assembled gap junction channels to allow the direct exchange of small molecules, including ions, neurotransmitters, and signaling molecules, which regulate the activities of the connected cells. Here, we investigate the role of Cx43 in the pathogenesis of prion diseases. Upregulated Cx43 expression, which was dependent on c-Jun N-Terminal Kinase (JNK)/c-Jun signaling cascades, was found in prion-affected brain tissues and hippocampal neuronal cells. Scrapie infection-induced Cx43 formed aggregated plaques within the cytoplasmic compartments at the cell-cell interfaces. The ethidium bromide (EtBr) uptake assay and scrape-loading dye transfer assay demonstrated that increased Cx43 has functional consequences for the activity of Cx43 hemichannels. Interestingly, blockade of PrPSc accumulation reduced Cx43 expression through the inhibition of JNK signaling, indicating that PrPSc accumulation may be directly involved in JNK activation-mediated Cx43 upregulation. Overall, our findings describe a scrapie infection-mediated novel regulatory signaling pathway of Cx43 expression and may suggest a role for Cx43 in the pathogenesis of prion diseases.
Keywords: Animals; Brain; Cell Membrane; Cells, Cultured; Connexin 43; Disease Models, Animal; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mesocricetus; Mice, Inbred C57BL; Mice, Knockout; PrPSc Proteins; RNA, Messenger; Scrapie; Up-Regulation

Usefulness of an Integrated Analysis of Different Memory Tasks to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease: The Episodic Memory Score (EMS). - Marra, Camillo; Gainotti, Guido; Fadda, Lucia; Perri, Roberta; Lacidogna, Giordano; Scaricamazza, Eugenia; Piccininni, Chiara; Quaranta, Davide (J Alzheimers Dis, 2016)
Taking into the account both the severity and the consistency of performances obtained on memory tests by patients with amnestic mild cognitive impairment (aMCI) could improve the power to predict their progression to Alzheimer's disease. For this purpose, we constructed the Episodic Memory Score (EMS), which is obtained by subdividing in tertiles performances obtained at baseline in verbal (RAVLT) and visual episodic memory (Rey-Osterrieth Figure-delayed recall) and giving a score ranging from 1 (worst result) to 3 (best result) to results falling within each tertile. The EMS was computed for each patient by summing the tertile score obtained on each memory task, so that the total score ranged from 4 (worst performance) to 12 (best performance). The aMCI sample consisted of 198 subjects who completed the two-year follow-up, at the end of which 55 subjects had converted to dementia. The mean EMS score obtained by aMCI converters was significantly lower than that of aMCI-stable patients. In detecting conversion to dementia, the comparison between EMS and individual memory scores obtained at baseline was made by computing ROC curves, and estimating the respective area under the curve (AUC). The EMS had a larger AUC than the individual memory scores. At baseline aMCI converters performed worse than non-converters not only on memory tasks, but also on executive functions tasks. However, in a multiple variables logistic regression analysis in which all scores showing statistically significant differences between aMCI-converters and aMCI-stable were entered, the EMS was the only reliable predictor of progression from aMCI to dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Disease Progression; Female; Humans; Logistic Models; Longitudinal Studies; Male; Memory, Episodic; Mental Recall; Neuropsychological Tests; ROC Curve

The Utilization of Retinal Nerve Fiber Layer Thickness to Predict Cognitive Deterioration. - Shi, Zhongyong; Zhu, Yingbo; Wang, Meijuan; Wu, Yujie; Cao, Jing; Li, Chunbo; Xie, Zhongcong; Shen, Yuan (J Alzheimers Dis, 2016)
Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4 ± 3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n = 60) or converted participants whose cognitive status deteriorated (n = 18). A logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762-0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849-0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59 ± 0.30 versus 0.12 ± 0.19, p <  0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer's disease.
Keywords: Aged; Cognition Disorders; Female; Humans; Logistic Models; Longitudinal Studies; Male; Nerve Fibers; Neuropsychological Tests; Predictive Value of Tests; Retina; ROC Curve; Statistics, Nonparametric; Tomography, Optical Coherence

Validation of a Commercial Chemiluminescence Immunoassay for the Simultaneous Measurement of Three Different Amyloid-β Peptides in Human Cerebrospinal Fluid and Application to a Clinical Cohort. - Klafki, Hans-W; Hafermann, Henning; Bauer, Chris; Haussmann, Ute; Kraus, Inga; Schuchhardt, Johannes; Muck, Stephan; Scherbaum, Norbert; Wiltfang, Jens (J Alzheimers Dis, 2016)
A comprehensive assay validation campaign of a commercially available chemiluminescence multiplex immunoassay for the simultaneous measurement of the amyloid-β peptides Aβ38, Aβ40, and Aβ42 in human cerebrospinal fluid (CSF) is presented. The assay quality parameters we addressed included impact of sample dilution, parallelism, lower limits of detection, lower limits of quantification, intra- and inter-assay repeatability, analytical spike recoveries, and between laboratory reproducibility of the measurements. The assay performed well in our hands and fulfilled a number of predefined acceptance criteria. The CSF levels of Aβ40 and Aβ42 determined in a clinical cohort (n = 203) were statistically significantly correlated with available ELISA data of Aβ1-40 (n = 158) and Aβ1-42 (n = 179) from a different laboratory. However, Bland-Altman method comparison indicated systematic differences between the assays. The data presented here furthermore indicate that the CSF concentration of Aβ40 can surrogate total CSF Aβ and support the hypothesis that the Aβ42/Aβ40 ratio outperforms CSF Aβ42 alone as a biomarker for Alzheimer's disease due to a normalization to total Aβ levels.

Validation of Immunoassay-Based Tools for the Comprehensive Quantification of Aβ40 and Aβ42 Peptides in Plasma. - Pérez-Grijalba, Virginia; Fandos, Noelia; Canudas, Jesús; Insua, Daniel; Casabona, Diego; Lacosta, Ana M; Montañés, María; Pesini, Pedro; Sarasa, Manuel (J Alzheimers Dis, 2016)
Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer's disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-β (Aβ) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident interpretation of clinical results. The aim of this study was to validate ELISA sandwich colorimetric ABtest40 and ABtest42 for the quantification of Aβ40 and Aβ42 in human plasma. The validation parameters assessed included precision, accuracy, sensitivity, specificity, recovery, and dilution linearity. ABtest40 and ABtest42 proved to be specific for their target peptide using Aβ peptides with sequence similar to the target. Mean relative error in the quantification was found to be below 7.5% for both assays, with high intra-assay, inter-assay, and inter-batch precision (CV <9.0% on average). Sensitivity was assessed by determination of the limit of quantification fulfilling precision and accuracy criteria; it was established at 7.60 pg/ml and 3.60 pg/ml for ABtest40 and ABtest42, respectively. Plasma dilution linearity was demonstrated in PBS; however, dilution in a proprietary formulated buffer significantly increased the recovery of both Aβ40 and Aβ42 masked by matrix interactions, allowing a more comprehensive assessment of the free and total peptide levels in the plasma. In conclusion, both assays were successfully validated as tools for the quantification Aβ40 and Aβ42 in plasma.

Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study. - Müller, Mareike; Kuiperij, H Bea; Versleijen, Alexandra A M; Chiasserini, Davide; Farotti, Lucia; Baschieri, Francesca; Parnetti, Lucilla; Struyfs, Hanne; De Roeck, Naomi; Luyckx, Jill; Engelborghs, Sebastiaan; Claassen, Jurgen A; et al. (J Alzheimers Dis, 2016)
MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer's disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.

Validation of the Spanish version of the Baylor Profound Mental Status Examination. - Salmerón, Sergio; Huedo, Isabel; López-Utiel, Melisa; Soler-Moratalla, Isabel; Flores-Ruano, Teresa; Fernández-Sánchez, Miguel; Noguerón, Alicia; Doody, Rachelle S; Abizanda, Pedro (J Alzheimers Dis, 2016)
BACKGROUND: There are no short valid instruments to evaluate cognitive status in severe Alzheimer's disease (AD) patients in the Spanish language. OBJECTIVE: To validate the Spanish version of the Baylor Profound Mental Status Examination (BPMSE-Sp). METHODS: The Baylor Profound Mental Status Examination (BPMSE) was translated to Spanish and back translated. Validation was conducted in 100 patients with severe probable AD with a Mini-Mental State Examination (MMSE) <12. We assessed internal consistency (Cronbach's alpha), concurrent validity (Pearson's correlations) with the MMSE, Severe Impairment Battery (SIB), Neuropsychiatric Inventory Short Form (NPI-Q) and the Functional Assessment Staging and reliability. RESULTS: The mean age of patients was 84.9; 74% were female; 64% were institutionalized. The mean MMSE was 5.6; the mean BPMSE-Sp was 13.6; the mean BPMSE-Sp behavior was 1.2; the mean SIB was 42.2; and the mean NPI-Q was 4.7. BPMSE-Sp presented good internal consistency (Cronbach α= 0.84). There were significant correlations between the BPMSE-Sp and MMSE (r = 0.86, p <  0.001), and between the BPMSE-Sp and SIB (r = 0.92, p <  0.001). Inter-rater and test-retest reliability were in both cases excellent, ranging between 0.96 and 0.99 (p <  0.001). BPMSE-Sp had fewer floor and ceiling effects than the MMSE. CONCLUSIONS: The BPMSE-Sp is a valid tool for use in daily practice and research in the evaluation of cognitive function of patients with severe AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Cognition Disorders; Female; Humans; Language; Male; Mental Status Schedule; Neuropsychological Tests; Reproducibility of Results; Severity of Illness Index; Spain

Validation of the Total Cerebrovascular Disease Burden Scale in a Community Sample. - Xu, Xin; Hilal, Saima; Collinson, Simon L; Chan, Qun Lin; Yi Chong, Eddie Jun; Ikram, Mohammad Kamran; Venketasubramanian, Narayanaswamy; Cheng, Ching-Yu; Wong, Tien Yin; Chen, Christopher Li-Hsian (J Alzheimers Dis, 2016)
BACKGROUND: A total cerebrovascular disease (CeVD) burden scale was previously constructed and an inverse association of CeVD burden and cognition was found. However, the generalizability of the CeVD scale has not been examined. OBJECTIVE: The objective was to validate the previously constructed total CeVD burden scale by establishing its association with cognitive function and dementia diagnosis in a community sample. METHODS: Eligible participants were assessed on an extensive neuropsychological battery and underwent MRI scans. The total CeVD scale, comprising markers of both small- and large-vessel diseases, was derived according to previously described criteria. Association of total CeVD burden with global and domain-based cognitive performance and dementia diagnostic utility of the scale was established. RESULTS: A total of 863 participants were included in the analysis. A stepwise association of CeVD burden score with global and domain-specific cognitive function was found. Per score increase on the total CeVD burden scale was associated with 3.6 (95% CI = 2.1-6.4) times higher odds of dementia compared to dementia-free. DISCUSSION: The total CeVD burden scale is associated with cognition and dementia in a community sample. Longitudinal studies are required to establish the predictive ability of this scale.

A Validation Study of Vascular Cognitive Impairment Genetics Meta-Analysis Findings in an Independent Collaborative Cohort. - Skrobot, Olivia Anna; McKnight, Amy Jayne; Passmore, Peter Anthony; Seripa, Davide; Mecocci, Patrizia; Panza, Francesco; Kalaria, Rajesh; Wilcock, Gordon; Munafò, Marcus; Erkinjuntti, Timo; Karhunen, Pekka; Pessi, Tanja; et al. (J Alzheimers Dis, 2016)
Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ4, ɛ2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax = 549) and elderly non-demented samples (nmax = 552). Where available, genotype data derived from Illumina's 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16-1.58, p = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42-0.90, p = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17-2.16, p = 0.003). Association was also observed with APOE epsilon alleles; ɛ4 (OR = 1.85, 95% CI 1.35-2.52, p = <0.0001) and ɛ2 (OR = 0.67, 95% CI 0.46-0.98, p = 0.03). Logistic regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ4 allele.

The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. - Jefferson, Angela L; Gifford, Katherine A; Acosta, Lealani Mae Y; Bell, Susan P; Donahue, Manus J; Davis, L Taylor; Gottlieb, JoAnn; Gupta, Deepak K; Hohman, Timothy J; Lane, Elizabeth M; Libon, David J; Mendes, Lisa A; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Blood Pressure Monitoring, Ambulatory; Brain; Case-Control Studies; Cerebral Angiography; Cognitive Dysfunction; Echocardiography; Epidemiologic Research Design; Female; Follow-Up Studies; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Research Design

Vascular Contributions in Alzheimer's Disease-Related Neuropathological Changes: First Autopsy Evidence from a South Asian Aging Population. - Wijesinghe, Printha; Shankar, S K; Yasha, T C; Gorrie, Catherine; Amaratunga, Dhammika; Hulathduwa, Sanjayah; Kumara, K Sunil; Samarasinghe, Kamani; Suh, Yoo-Hun; Steinbusch, Harry W M; De Silva, K Ranil D (J Alzheimers Dis, 2016)
BACKGROUND: Evidence from various consortia on vascular contributions has been inconsistent in determining the etiology of sporadic Alzheimer's disease (AD). OBJECTIVE: To investigate vascular risk factors and cerebrovascular pathologies associated in manifestation of AD-related neuropathological changes of an elderly population. METHODS: Postmortem brain samples from 76 elderly subjects (≥50 years) were used to study genetic polymorphisms, intracranial atherosclerosis of the circle of Willis (IASCW), and microscopic infarcts in deep white matters. From this cohort, 50 brains (≥60 years) were subjected to neuropathological diagnosis using immunohistopathological techniques. RESULTS: Besides the association with age, the apolipoprotein E ɛ4 allele was significantly and strongly associated with Thal amyloid-β phases ≥1 [odds ratio (OR) = 6.76, 95% confidence interval (CI) 1.37-33.45] and inversely with Braak neurofibrillary tangle (NFT) stages ≥III (0.02, 0.0-0.47). Illiterates showed a significant positive association for Braak NFT stages ≥IV (14.62, 1.21-176.73) and a significant negative association for microscopic infarcts (0.15, 0.03-0.71) in deep white matters. With respect to cerebrovascular pathologies, cerebral small vessel lesions (white matter hyperintensities and cerebral amyloid angiopathy) showed a higher degree of associations among them and with AD-related neuropathological changes (p < 0.05) compared to large vessel pathology (IASCW), which showed a significant association only with Braak NFT stages ≥I (p = 0.050). CONCLUSION: These findings suggest that besides age, education, and genetic factors, other vascular risk factors were not associated with AD-related neuropathological changes and urge prompt actions be taken against cerebral small vessel diseases since evidence for effective prevention is still lacking.

Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies. - Lim, Shir Lynn; Gao, Qi; Nyunt, Ma Shwe Zin; Gong, Lingli; Lunaria, Josephine B; Lim, May Li; Ling, Audrey; Lam, Carolyn Su-Ping; Richards, Arthur Mark; Ling, Lieng Hsi; Ng, Tze Pin (J Alzheimers Dis, 2016)
BACKGROUND: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease. OBJECTIVE: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases. METHODS: Cognition was assessed by Mini-Mental State Examination (MMSE) (n = 308) and detailed neuropsychological tests (n = 155). Vascular measures included carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (β), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors. RESULTS: The participants' mean age was 63.0 ± 6.1 years. Inverse associations with MMSE were found for AC (β= 0.128, p = 0.019), Ep (β= -0.151, p = 0.008), β index (β= -0.122, p = 0.029), carotid stiffness z-score (β= -0.154, p = 0.007); with executive function for CFPWV (β= -0.209, p = 0.026), AC (β= 0.214, p = 0.005), Ep (β= -0.160, p = 0.050), β index (β= -0.165, p = 0.041), and both aortic (β= -0.229, p = 0.010) and carotid (β= -0.208, p = 0.010) stiffness z-scores; with verbal memory for AI (β= -0.229, p = 0.004) and aortic (β= -0.263, p = 0.004) stiffness z-score; with language for AI (β= -0.155, p = 0.025), aortic stiffness z-score (β= -0.196, p = 0.011). RHI positively correlated with visuospatial ability (β= 0.195, p = 0.013) and executive function (β= 0.151, p = 0.045). CONCLUSION: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment.
Keywords: Aged; Blood Flow Velocity; Blood Pressure; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cognitive Aging; Female; Humans; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Singapore; Vascular Stiffness

Vascular Risk Factors and Cognition in Parkinson's Disease. - Pilotto, Andrea; Turrone, Rosanna; Liepelt-Scarfone, Inga; Bianchi, Marta; Poli, Loris; Borroni, Barbara; Alberici, Antonella; Premi, Enrico; Formenti, Anna; Bigni, Barbara; Cosseddu, Maura; Cottini, Elisabetta; et al. (J Alzheimers Dis, 2016)
Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson's disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.
Keywords: Age of Onset; Aged; Attention; Disability Evaluation; Educational Status; Executive Function; Female; Humans; Male; Motor Activity; Neuropsychological Tests; Parkinson Disease; Prevalence; Risk Factors; Sex Factors; Time Factors; Vascular Diseases

Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder. - Takahashi, Sho; Mizukami, Katsuyoshi; Arai, Tetsuaki; Ogawa, Ryoko; Kikuchi, Norihiro; Hattori, Satoshi; Darby, David; Asada, Takashi (J Alzheimers Dis, 2016)
BACKGROUND: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB. OBJECTIVE: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD. METHODS: Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy. RESULTS: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters. CONCLUSION: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB.
Keywords: 3-Iodobenzylguanidine; Aged; Aged, 80 and over; Depressive Disorder, Major; Follow-Up Studies; Heart Rate; Humans; Hypercapnia; Hypotension, Orthostatic; Kaplan-Meier Estimate; Lewy Body Disease; Middle Aged; Partial Pressure; Psychiatric Status Rating Scales; Retrospective Studies; Ventilators, Mechanical

Vitamin D and Memory Decline: Two Population-Based Prospective Studies. - Kuźma, Elżbieta; Soni, Maya; Littlejohns, Thomas J; Ranson, Janice M; van Schoor, Natasja M; Deeg, Dorly J H; Comijs, Hannie; Chaves, Paulo H M; Kestenbaum, Bryan R; Kuller, Lewis H; Lopez, Oscar L; Becker, James T; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown. OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline. METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively. RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34). CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.
Keywords: Humans; Memory Disorders; Netherlands; Prospective Studies; United States; Vitamin D; Vitamin D Deficiency

Vitamin D, Cognition and Alzheimer's Disease: The Therapeutic Benefit is in the D-Tails. - Landel, Véréna; Annweiler, Cedric; Millet, Pascal; Morello, Maria; Féron, François (J Alzheimers Dis, 2016)
Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer's disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider.

Vitamin D Supplementation Appears to Increase Plasma Aβ40 in Vitamin D Insufficient Older Adults: A Pilot Randomized Controlled Trial. - Miller, Brendan J; Whisner, Corrie M; Johnston, Carol S (J Alzheimers Dis, 2016)
Low plasma amyloid-β (Aβ) is linked to Alzheimer's disease. Since vitamin D cleared brain Aβ in vitro, this 8-week trial examined whether vitamin D increased plasma Aβ40. Vitamin D insufficient adults (6/18 M/F; 64.3 ± 10.9 y) were randomized to placebo or vitamin (50,000 IU/week) treatments. The vitamin group experienced greater plasma Aβ40 change than controls, +14.9 ± 12.0 and +12.8 ± 12.8 pg/mL (p = 0.045; effect size, 0.228). Change in Aβ40 for older participants (≥60 y) was +18.3 ± 33.6 and -3.2 ± 44.5 pg/mL for vitamin (n = 4) and placebo (n = 4) groups (effect size, 0.295). Thus, vitamin D may increase plasma Aβ, particularly in older adults, suggesting decreased brain Aβ.

Volumetric and shape analysis of the thalamus and striatum in amnestic mild cognitive impairment. - Leh, Sandra E; Kälin, Andrea M; Schroeder, Clemens; Park, Min Tae M; Chakravarty, M Mallar; Freund, Patrick; Gietl, Anton F; Riese, Florian; Kollias, Spyros; Hock, Christoph; Michels, Lars (J Alzheimers Dis, 2016)
Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer's disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n = 16) to healthy subjects (CS, n = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate "classical" cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Corpus Striatum; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thalamus

What are the Most Frequently Impaired Markers of Neurodegeneration in ADNI Subjects? - Andriuta, Daniela; Moullart, Véronique; Schraen, Susanna; Devendeville, Agnes; Meyer, Marc-Etienne; Godefroy, Olivier (J Alzheimers Dis, 2016)
The aim of this study was to examine the relationship between cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer's disease (AD) (Aβ1-42, t-tau, and p-tau) and 18Fluorodeoxyglucose positron emission tomography (FDG-PET) hypometabolism in subjects from the Alzheimer's Disease Neuroimaging Initiative, and specifically to determine which index of neurodegeneration was most frequently affected. The secondary objective was to determine the most frequently hypometabolic region in patients with a CSF AD signature (abnormal Aβ1-42 and abnormal p-tau). We included the 372 subjects (85 normal subjects, 212 patients with mild cognitive impairment, and 75 patients with AD) with a CSF biomarker dosage (Aβ1-42, t-tau, and p-tau) and brain FDG-PET. The relationship between FDG-PET metabolism (in five regions of interest (ROI) known to be damaged in AD) and CSF t-tau and p-tau levels was studied as a function of CSF Aβ1-42 status. FDG-PET hypometabolism and CSF t-tau and p-tau levels were correlated only in patients with an abnormal CSF Aβ1-42 level (t-tau: R2 = 0.044, p = 0.001; p-tau: R2 = 0.02, p = 0.03). In the latter patients, CSF p-tau was the most frequently (p = 0.0001) abnormal neurodegeneration marker (p-tau: 92.8%; FDG-PET: 56.5%; CSF t-tau: 59.1%). Within the five ROI of FDG PET, the angular gyrus metabolism (R2 = 0.149; p = 0.0001) was selected as the most tightly associated with CSF AD signature. The relation between CSF markers of neurodegeneration (p-tau and t-tau) and brain hypometabolism (in FDG-PET) is conditioned by presence of amyloid abnormality. This finding supports the current physiopathological model of AD. P-tau is the most frequently impaired biomarker. Using FDG PET angular gyrus hypometabolism is the most sensitive to CSF-biomarker-defined AD.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Cognitive Dysfunction; Databases, Factual; Female; Fluorodeoxyglucose F18; Humans; Male; Peptide Fragments; Phosphorylation; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins

White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer's Disease. - Sánchez-Valle, Raquel; Monté, Gemma C; Sala-Llonch, Roser; Bosch, Beatriz; Fortea, Juan; Lladó, Albert; Antonell, Anna; Balasa, Mircea; Bargalló, Nuria; Molinuevo, José Luis (J Alzheimers Dis, 2016)
PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p <  0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p <  0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.
Keywords: Adult; Aging; Alzheimer Disease; Brain; Cohort Studies; Diffusion Tensor Imaging; Disease Progression; Family; Female; Heterozygote; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Mutation; Neuropsychological Tests; Organ Size; Presenilin-1; White Matter

White Matter and Hippocampal Volume Predict the Risk of Dementia in Patients with Cerebral Small Vessel Disease: The RUN DMC Study. - van Uden, Ingeborg W M; van der Holst, Helena M; Tuladhar, Anil M; van Norden, Anouk G W; de Laat, Karlijn F; Rutten-Jacobs, Loes C A; Norris, David G; Claassen, Jurgen A H R; van Dijk, Ewoud J; Kessels, Roy P C; de Leeuw, Frank-Erik (J Alzheimers Dis, 2016)
BACKGROUND: The relationship between cerebral small vessel disease (SVD) and dementia has been studied without considering white matter (WM) volume, the microstructural integrity of the WM surrounding the SVD, and grey matter (GM). OBJECTIVE: We prospectively investigated the relationship between these structures and the risk of dementia, and formed a prediction model to investigate which characteristics (macro- or microstructural) explained most of the variance. METHODS: The RUN DMC study is a prospective cohort study among 503 non-demented participants with an age between 50 and 85 years at baseline, with baseline assessment in 2006 and follow-up assessment in 2012. Two were lost to follow-up (yielding a 99.6% response-rate). Cox regression analysis was used, to calculate hazard ratios for dementia, of baseline MRI characteristics. Tract-Based Spatial Statistics (TBSS) analysis was used to assess the added value of microstructural integrity of the WM. RESULTS: Mean age at baseline was 65.6 years (SD 8.8) and 56.8% was male. 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95% CI 7.7-14.6). Low WM and hippocampal volume are significant predictors for dementia. WM, WM hyperintensities, and hippocampal volume explained most of the variance. TBSS analyses showed no additional value of diffusion parameters. CONCLUSIONS: WM and hippocampal volume were the main predictors for the development of incident dementia at 5-year follow-up in elderly with SVD. There was no additional diagnostic value of the diffusion tensor imaging parameters on top of the macrostructural characteristics.
Keywords: Aged; Cerebral Small Vessel Diseases; Cohort Studies; Dementia; Diffusion Tensor Imaging; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Statistics, Nonparametric; White Matter

White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease. - Coutu, Jean-Philippe; Goldblatt, Alison; Rosas, H Diana; Salat, David H (J Alzheimers Dis, 2016)
White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.
Keywords: Aged; Aging; Alzheimer Disease; Cognitive Dysfunction; Diffusion Tensor Imaging; Factor Analysis, Statistical; Female; Hippocampus; Humans; Imaging, Three-Dimensional; Male; Mental Status Schedule; Neuropsychological Tests; White Matter

Within-Individual Variability: An Index for Subtle Change in Neurocognition in Mild Cognitive Impairment. - Roalf, David R; Quarmley, Megan; Mechanic-Hamilton, Dawn; Wolk, David A; Arnold, Steven E; Moberg, Paul J (J Alzheimers Dis, 2016)
BACKGROUND: The transition from mild cognitive impairment (MCI) to Alzheimer's disease is characterized by a decline in cognitive performance in many domains. Cognitive performance profiles in MCI are heterogeneous, however, and additional insights into markers of incipient dementia are needed. Typically, studies focus on average or mean performance, but ignore consistency of performance across domains. WIV (within-individual variability) provides an index of this consistency and is a potential marker of cognitive decline. OBJECTIVE: To use neurocognitive data from the Alzheimer's Disease Neuroimaging Initiative cohort to measure neurocognitive variability. METHODS: The utility of WIV was measured, in addition to global neurocognitive performance (GNP), for identifying AD and MCI. In addition, the association between changes in neurocognitive variability and diagnostic transition over 12 months was measured. RESULTS: As expected, variability was higher in AD and MCI as compared to healthy controls; GNP was lower in both groups as compared to healthy subjects. Global neurocognitive performance alone best distinguished those with dementia from healthy older adults. Yet, for individuals with MCI, including variability along with GNP improved diagnostic classification. Variability was higher at baseline in individuals transitioning from MCI to AD over a 12-month period. CONCLUSION: We conclude that variability offers complementary information about neurocognitive performance in dementia, particularly in individuals with MCI, and may provide beneficial information about disease transition.

Yokukansan in the Treatment of Behavioral and Psychological Symptoms of Dementia: An Updated Meta-Analysis of Randomized Controlled Trials. - Matsunaga, Shinji; Kishi, Taro; Iwata, Nakao (J Alzheimers Dis, 2016)
BACKGROUND: Previous clinical studies found that yokukansan has a therapeutic effect on behavioral and psychological symptoms of dementia (BPSD) in dementia patients. OBJECTIVE: To perform an updated meta-analysis of randomized controlled trials (RCTs) testing yokukansan for patients with BPSD. METHODS: Primary efficacy and safety endpoints were BPSD total scores and all-cause discontinuation, respectively. Secondary outcomes were BPSD subscales, cognitive function scores [Mini-mental state examination (MMSE)], activities of daily living (ADL) scores, discontinuation due to adverse events (AEs), and incidences of AEs. RESULTS: Five RCTs with 381 patients with BPSD were included. Compared with controls [placebo+usual care (UC)], yokukansan significantly decreased BPSD total scores [standardized mean difference (SMD) = -0.32, 95% confidence interval (CI) = -0.53 to -0.11, p = 0.003, I2 = 0%, N = 5 studies, n = 361]. Yokukansan was more efficacious in reducing BPSD subscale scores (delusions: SMD = -0.51, 95% CI = -0.98 to -0.04, hallucinations: SMD = -0.54, 95% CI = -0.96 to -0.12, agitation/aggression: SMD = -0.37, 95% CI = -0.60 to -0.15) than placebo+UC. However, yokukansan was not superior to placebo+UC for BPSD total as well as any subscales scores only in Alzheimer's disease patients. Compared with UC, yokukansan treatment improved ADL scores (SMD = -0.32, 95% CI = -0.62 to -0.01). MMSE scores did not differ between the yokukansan and placebo+UC treatment groups. No significant differences were found in all-cause discontinuation, discontinuation due to AEs, and incidences of AEs between yokukansan and placebo+UC treatments. CONCLUSIONS: Our results suggest that yokukansan is beneficial for the treatment of patients with BPSD and is well-tolerated; it was not beneficial for BPSD total and any subscale scores only in Alzheimer's disease patients.

The Zebrafish Equivalent of Alzheimer's Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress. - Ebrahimie, Esmaeil; Moussavi Nik, Seyyed Hani; Newman, Morgan; Van Der Hoek, Mark; Lardelli, Michael (J Alzheimers Dis, 2016)
Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer's disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2, PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ-secretase activity and suppress the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology.

Zinc-Mediated Binding of Nucleic Acids to Amyloid-β Aggregates: Role of Histidine Residues. - Khmeleva, Svetlana A; Radko, Sergey P; Kozin, Sergey A; Kiseleva, Yana Y; Mezentsev, Yuri V; Mitkevich, Vladimir A; Kurbatov, Leonid K; Ivanov, Alexis S; Makarov, Alexander A (J Alzheimers Dis, 2016)
Amyloid-β peptide (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Besides extracellular Aβ, intraneuronal Aβ (iAβ) has been suggested to contribute to AD onset and development. Based on reported in vitro Aβ-DNA interactions and nuclear localization of iAβ, the interference of iAβ with the normal DNA expression has recently been proposed as a plausible pathway by which Aβ can exert neurotoxicity. Employing the sedimentation assay, thioflavin T fluorescence, and dynamic light scattering we have studied effects of zinc ions on binding of RNA and single- and double-stranded DNA molecules to Aβ42 aggregates. It has been found that zinc ions significantly enhance the binding of RNA and DNA molecules to pre-formed β-sheet rich Aβ42 aggregates. Another type of Aβ42 aggregates, the zinc-induced amorphous aggregates, was demonstrated to also bind all types of nucleic acids tested. To evaluate the role of the Aβ metal-binding domain's histidine residues in Aβ-nucleic acid interactions mediated by zinc, Aβ16 mutants with substitutions H6R and H6A-H13A and rat Aβ16 lacking histidine residue 13 were used. The zinc-induced interaction of Aβ16 with DNA was shown to critically depend on histidine residues 6 and 13. However, the inclusion of H6R mutation in Aβ42 peptide did not affect DNA binding to Aβ42 aggregates. Since oxidative and/or nitrosative stresses implicated in AD pathogenesis are known to release zinc ions from metallothioneins in cytoplasm and cell nuclei, our findings suggest that intracellular zinc can be an important player in iAβ-nucleic acid interactions.

δ Scores are Exportable Across Cultural and Linguistic Boundaries. - Royall, Donald R; Palmer, Raymond F; Matsuoka, Teruyuki; Kato, Yuka; Taniguchi, Shogo; Ogawa, Mayu; Fujimoto, Hiroshi; Okamura, Aiko; Shibata, Keisuke; Nakamura, Kaeko; Nakaaki, Shutaro; Koumi, Hiroyuki; et al. (J Alzheimers Dis, 2016)
The latent variable "δ", can accurately diagnose dementia. Its generalizability across populations is unknown. We constructed a δ homolog ("dT2J") in data collected by the Texas Alzheimer's Research and Care Consortium (TARCC). From this, we calculated a composite d-score "d". We then tested d's generalizability across random subsets of TARCC participants and to a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (AD) (n = 176). dT2J was indicated by Instrumental Activities of Daily Living and psychometric measures. Embedded in this battery were the Mini-Mental Status Examination (MMSE) and an executive clock-drawing task (CLOX). Only MMSE and CLOX were available in both TARCC and the Japanese cohort. Therefore, a second composite variable, "T2J", was constructed solely from the factor loadings of CLOX and MMSE on d. The diagnostic accuracy of T2J was estimated in the validation sample, the remainder of the TARCC cohort, and in the Japanese sample. The areas under the receiver operating curve (AUC; ROC) for T2J were compared in each sample, and against d in TARCC. The AUCs for T2J were statistically indiscriminable within TARCC, and in Japanese persons. In Japanese persons, AUCs for T2J were 0.97 for the discrimination between AD versus NC, 0.86 for AD versus MCI, and 0.79 for NC versus MCI. The AUCs for T2J in Japanese persons were higher than any individual psychometric measure in that sample. Valid d-score composites can be abstracted from a subset of δ's indicators. Moreover, those composites are exportable across cultural and linguistic boundaries.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Asian Continental Ancestry Group; Cognitive Dysfunction; Cohort Studies; Culture; Executive Function; Female; Humans; Linguistics; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Psychometrics; Reproducibility of Results; ROC Curve; Texas

Acute Exposure of the Mediobasal Hypothalamus to Amyloid-β25-35 Perturbs Hepatic Glucose Metabolism. - Arrieta-Cruz, Isabel; Knight, Colette M; Gutiérrez-Juérez, Roger (J Alzheimers Dis, 2015)
Patients with Alzheimer's disease (AD) have a higher risk for developing insulin resistance and diabetes. Amyloid plaques, a hallmark of AD, are composed of amyloid-β (Aβ). Because the mediobasal hypothalamus controls hepatic glucose production, we examined the hypothesis that its exposure to Aβ perturbs the regulation of glucose metabolism. The infusion of Aβ25-35, but not its scrambled counterpart, into the mediobasal hypothalamus of young rats, increased circulating glucose as a consequence of enhanced hepatic glucose production during pancreatic clamp studies. These findings suggest a link between AD and alterations of glucose metabolism.

Adipose Tissue Distribution in Patients with Alzheimer's Disease: A Whole Body MRI Case-Control Study. - Diehl-Wiesenecker, Eva; von Armin, Christine A F; Dupuis, Luc; Müller, Hans-Peter; Ludolph, Albert C; Kassubek, Jan (J Alzheimers Dis, 2015)
BACKGROUND: Total and central adiposity have been associated with increased risk of Alzheimer's disease (AD). Visceral and subcutaneous adipose tissues have different metabolic characteristics and could therefore be differentially associated with AD. OBJECTIVE: To compare regional fat distribution determined by magnetic resonance imaging (MRI) in AD patients and healthy controls and investigate associations with stage of the disease and chemical markers. The investigation was performed in a prospective case-control study. METHODS: We examined thirty patients with mild to moderate AD by whole-body MRI (1.5 T) and clinical questionnaires in comparison to thirty cognitively healthy age- and gender-matched study participants. Volumes of total, subcutaneous, and visceral body fat tissue were determined by an unbiased automatic analysis algorithm. Levels of leptin, ghrelin, and adiponectin were determined in serum, amyloid-β (Aβ)1-42 and tau protein levels in cerebrospinal fluid (CSF). RESULTS: Male AD patients displayed significantly more total fat tissue than male controls. This difference was not observed in women. We observed a trend toward higher volume of visceral fat tissue in all patients (p = 0.13). Severity of disease was not associated with fat distribution in our study. Increased leptin levels correlated with lower CSF Aβ 1-42 in female, but not in male, AD patients. CONCLUSIONS: Fat volume is increased in male, but not in female AD patients. Negative correlation of leptin levels and CSF Aβ 1-42 in females might be one co-factor for the increased AD risk of females. Further studies are required to confirm this gender difference in fat volume during AD and evaluate its pathophysiological importance.

Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. - Li, Qiao-Xin; Villemagne, Victor L; Doecke, James D; Rembach, Alan; Sarros, Shannon; Varghese, Shiji; McGlade, Amelia; Laughton, Katrina M; Pertile, Kelly K; Fowler, Christopher J; Rumble, Rebecca L; Trounson, Brett O; et al. (J Alzheimers Dis, 2015)
BACKGROUND: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. METHODS: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. RESULTS: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity. CONCLUSIONS: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus. - Herukka, Sanna-Kaisa; Rummukainen, Jaana; Ihalainen, Jouni; von Und Zu Fraunberg, Mikael; Koivisto, Anne M; Nerg, Ossi; Puli, Lakshman K; Seppälä, Toni T; Zetterberg, Henrik; Pyykkö, Okko T; Helisalmi, Seppo; Tanila, Heikki; et al. (J Alzheimers Dis, 2015)
Background: Amyloid-β (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1-42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1-42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1-42 levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.

Analysis of the Inhibitory Elements in the p5 Peptide Fragment of the CDK5 Activator, p35, CDKR1 Protein. - Binukumar, B K; Shukla, Varsha; Amin, Niranjana D; Bhaskar, Manju; Skuntz, Suzanne; Steiner, Joseph; Winkler, Dirk; Pelech, Steven L; Pant, Harish C (J Alzheimers Dis, 2015)
Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles, it is well documented that cyclin-dependent kinase 5 (CDK5), a critical neuronal protein kinase in nervous system development, function, and survival, when deregulated and hyperactivated induces Alzheimer's disease (AD) and amyotrophic lateral sclerosis and Parkinson's disease-like phenotypes in mice. In a recent study, we demonstrated that p5, a small, truncated fragment of 24 amino acid residues derived from the CDK5 activator protein 35 (NCK5A, p35), selectively inhibited deregulated CDK5 hyperactivity and ameliorated AD phenotypes in model mice. In this study, we identified the most inhibitory elements in the p5 peptide fragment. Each amino acid residue in p5 was systematically replaced with its homologous residues that may still be able to functionally substitute. The effects of these p5 peptide analogs were studied on the phosphotransferase activities of CDK5/p35, CDK5/p25, ERK1, and GSK3β. The mimetic p5 peptide (A/V substitution at the C-terminus of the peptide) in the sequence, KNAFYERALSIINLMTSKMVQINV (p5-MT) was the most effective inhibitor of CDK5 kinase activity of 79 tested mimetic peptides including the original p5 peptide, KEAFWDRCLSVINLMSSKMLQINA (p5-WT). Replacement of the residues in C-terminus end of the peptide affected CDK5 phosphotransferase activity most significantly. These peptides were strong inhibitors of CDK5, but not the related proline-directed kinases, ERK1 and GSK3β.

Ankle-Brachial Index but Neither Intima Media Thickness Nor Coronary Artery Calcification is Associated With Mild Cognitive Impairment. - Weimar, Christian; Winkler, Angela; Dlugaj, Martha; Lehmann, Nils; Hennig, Frauke; Bauer, Marcus; Kröger, Knut; Kälsch, Hagen; Mahabadi, Amir-Abass; Dragano, Nico; Moebus, Susanne; Hoffmann, Barbara; et al. (J Alzheimers Dis, 2015)
BACKGROUND: Several studies have reported an association of atherosclerosis with mild cognitive impairment (MCI) and dementia independent of cardiovascular risk factors. OBJECTIVE: To compare the cross-sectional association of the ankle-brachial index (ABI), intima media thickness (IMT), and coronary artery calcification (CAC) with MCI and its subtypes, amnestic MCI (aMCI) and non-amnestic MCI (naMCI) in the population-based Heinz Nixdorf Recall cohort study. METHODS: 4,086 participants performed a validated brief cognitive assessment at the first follow-up examination (2006-2008). MCI was diagnosed according to previously published criteria. Prevalence ratio (PR) regression models adjusted for age, gender, education, cardiovascular risk factors, and APOE genotype were used to compare the association of the ABI, the CAC-Agatston score and the IMT with MCI and its subtypes. RESULTS: We identified 490 participants with MCI (mean age 66.1 ± 7.8, 46.9 % male, aMCI n = 249, naMCI n = 241) and 1,242 cognitively normal participants. A decreasing ABI (per 0.1) was significantly associated with a higher MCI prevalence in fully adjusted models (PR 1.06; 95% confidence interval (CI) 1.01-1.11), whereas an increasing CAC (log(CAC+1)) or IMT (per 0.1 mm) were not associated after adjustment. A decreasing ABI was also significantly associated with naMCI in fully adjusted models (PR 1.12; CI 1.03-1.21) but not with aMCI. CONCLUSIONS: Our data show that the degree of generalized atherosclerosis as measured by the ABI is associated with MCI and with naMCI in a population-based cohort.

APOE Affects the Volume and Shape of the Amygdala and the Hippocampus in Mild Cognitive Impairment and Alzheimer's Disease: Age Matters. - Tang, Xiaoying; Holland, Dominic; Dale, Anders M; Miller, Michael I (J Alzheimers Dis, 2015)
This paper examines how age intervenes in the effects of APOE ɛ4 allele on the volume and shape morphometrics of the hippocampus and the amygdala in mild cognitive impairment (MCI) and Alzheimer's disease. We evaluate the structural morphological differences between ɛ4 carriers and non-carriers in two age-dependent subgroups; younger than 75 years (Young-Old) and older than 80 years (Very-Old). While we show that the four structures of interest atrophy significantly in the ɛ4 carriers, relative to the non-carriers, of the Young-Old group, this effect is not observed in their Very-Old counterparts. The structures in the right hemisphere are found to be more affected by the APOE genotype than those in the left hemisphere and we identify the relevant regions in which significant atrophy occurs to be parts of the basolateral, centromedial, and lateral nucleus subregions of the amygdala and the CA1 and subiculum subregions of the hippocampus. We also observe that the APOE genotype only affects MCI patients that deteriorated to dementia within 3 years while leaving their "non-converting" counterparts unaffected.

The APOE Gene is Differentially Methylated in Alzheimer's Disease. - Foraker, Jessica; Millard, Steven P; Leong, Lesley; Thomson, Zachary; Chen, Sunny; Keene, C Dirk; Bekris, Lynn M; Yu, Chang-En (J Alzheimers Dis, 2015)
The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer's disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.

AβPP-Transgenic 2576 Mice Mimic Cell Type-Specific Aspects of Acetyl-CoA-Linked Metabolic Deficits in Alzheimer's Disease. - Bielarczyk, Hanna; Jankowska-Kulawy, Agnieszka; Hofling, Corinna; Ronowska, Anna; Gul-Hinc, Sylwia; Rossner, Steffen; Schliebs, Reinhard; Pawelczyk, Tadeusz; Szutowicz, Andrzej (J Alzheimers Dis, 2015)
The pyruvate-derived acetyl-CoA is a principal direct precursor substrate for bulk energy synthesis in the brain. Deficits of pyruvate dehydrogenase in the neocortex are common features of Alzheimer's disease and other age-related encephalopathies in humans. Therefore, amyloid-β overload in brains of diverse transgenic Alzheimer's disease model animals was investigated as one of neurotoxic compounds responsible for pyruvate dehydrogenase inhibition yielding deficits of cholinergic neurotransmission and cognitive functions. Brains of aged, 14-16-month-old Tg2576 mice contained 0.6 μmol/kg levels of amyloid-β 1-42. Activities of pyruvate dehydrogenase complex, choline acetyltransferase, and several enzymes of acetyl-CoA and energy metabolism were found to be unchanged in both forebrain mitochondria and synaptosomes of Tg2576 mice, indicating preservation of structural integrity at least cholinergic neuronal cells. However, in transgenic brain synaptosomes, pyruvate utilization, mitochondrial levels, and cytoplasmic acetyl-CoA levels, as well as acetylcholine content and its quantal release, were all found to be decreased by 25-40% . On the contrary, activation of pyruvate utilization was detected and no alterations in acetyl-CoA content and citrate or α-ketoglutarate accumulation were observed in transgenic whole brain mitochondria. These data indicate that amyloid-β evoked deficits in acetyl-CoA are confined to mitochondrial and cytoplasmic compartments of Tg2576 nerve terminals, becoming early primary signals paving path for further stages of neurodegeneration. On the other hand, acetyl-CoA synthesis in mitochondrial compartments of glial cells seems to be activated despite amyloid-β accumulated in transgenic brains.

Blood Protein Markers of Neocortical Amyloid-β Burden: A Candidate Study Using SOMAscan Technology. - Voyle, Nicola; Baker, David; Burnham, Samantha C; Covin, Antonia; Zhang, Zhanpan; Sangurdekar, Dipen P; Tan Hehir, Cristina A; Bazenet, Chantal; Lovestone, Simon; Kiddle, Steven; Dobson, Richard J B (J Alzheimers Dis, 2015)
BACKGROUND: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-β burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer's disease (AD) therapeutics. OBJECTIVE: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort. METHODS: Our study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOE ε4 carriage were used as covariates for all analysis. RESULTS: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects. CONCLUSIONS: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of further replication, further studies are required.

A Blood-Based, 7-Metabolite Signature for the Early Diagnosis of Alzheimer's Disease. - Olazarán, Javier; Gil-de-Gómez, Luis; Rodríguez-Martín, Andrés; Valentí-Soler, Meritxell; Frades-Payo, Belén; Marín-Muñoz, Juan; Antúnez, Carmen; Frank-García, Ana; Jiménez, Carmen Acedo; Gracia, Lorenzo Morlén; Torregrossa, Roberto Petidier; Guisasola, María Concepción; et al. (J Alzheimers Dis, 2015)
Accurate blood-based biomarkers of Alzheimer's disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid (22:6n-3, DHA), one bile acid (deoxycholic acid), one phosphatidylethanolamine [PE(36:4)], and one sphingomyelin [SM(39:1)]. Detailed analysis ruled out the influence of potential confounding variables, including comorbidities and treatments, on each of the seven biomarkers. The final model accurately distinguished AD from NC patients (AUC, 0.918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples.

Body Mass Index and Mortality Rate in Korean Patients with Alzheimer's Disease. - Jang, Hyemin; Kim, Jong Hun; Choi, Seong Hye; Lee, Yunhwan; Hong, Chang Hyung; Jeong, Jee Hyang; Han, Hyun Jeong; Moon, So Young; Park, Kyung Won; Han, Seol-Hee; Park, Kee Hyung; Kim, Hee Jin; et al. (J Alzheimers Dis, 2015)
Background: A relationship between body weight, cognitive impairment, and the onset of Alzheimer's disease (AD) was recently reported. However, to our knowledge, no studies have investigated the relationship between body weight and mortality in Asian AD patients. Objective: We evaluated the relationship between body mass index (BMI) and mortality rate in Korean AD cohorts. Methods: Participants were consecutively included from two Korean representative registries: 579 AD patients from Samsung Medical Center and 1911 AD patients from the Clinical Research Center for Dementia of South Korea study. We combined these two AD cohorts to evaluate the association between BMI and mortality. BMI was used to categorize the participants into underweight, normal-weight, overweight, and obesity subgroups. All deaths were confirmed through the nationwide mortality database of Statistics Korea. Results: 53 of 181 (29.3%), 208 of 1,127 (18.5%), 88 of 626 (14.1%), and 115 of 556 (20.7%) patients died in the underweight, normal-weight, overweight, and obese subgroups during 43.7 months of follow-up. The time-dependent cox proportional hazards model showed that, relative to the normal-weight subgroup, the underweight group had higher mortality (HR 1.82 (95% CI, 1.07-3.09)) while overweight group had lower mortality rate (HR 0.60 (95% CI, 0.38-0.95)) The effects of underweight and overweight were prominent in younger and older elderly group, respectively. However, there were no interactive effects of dementia severity or gender and BMI on survival rate. Conclusion: Relative to AD patients of normal weight, those who were underweight had an increased mortality rate, and overweight predicted decreased mortality in AD patients. Furthermore, our findings may help facilitate mortality stratification in AD patients by using baseline BMI.

Buccal Cell Cytokeratin 14 Correlates with Multiple Blood Biomarkers of Alzheimer's Disease Risk. - Leifert, Wayne R; Nguyen, Tori; Rembach, Alan; Martins, Ralph; Rainey-Smith, Stephanie; Masters, Colin L; Ames, David; Rowe, Christopher C; Macaulay, S Lance; François, Maxime; Fenech, Michael F (J Alzheimers Dis, 2015)
Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as Alzheimer's disease (AD). Our hypothesis was that cytokeratin 14 (CK14) expression could be used with blood-based biomarkers such as homocysteine, vitamin B12, and folate to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Buccal cells from 54 individuals were analyzed by a newly developed method that is rapid, automated, and quantitative for buccal cell CK14 expression levels. CK14 was negatively correlated with plasma Mg2 + and LDL, while positively correlated with vitamin B12, red cell hematocrit/volume, and basophils in the MCI group and positively correlated with insulin and vitamin B12 in the AD group. The combined biomarker panel (CK14 expression, plasma vitamin B12, and homocysteine) was significantly lower in the MCI (p = 0.003) and AD (p = 0.0001) groups compared with controls. Receiver-operating characteristic curves yielded area under the curve (AUC) values of 0.829 for the MCI (p = 0.002) group and 0.856 for the AD (p = 0.0003) group. These complex associations of multiple related parameters highlight the differences between the MCI and AD cohorts and possibly an underlying metabolic pathology associated with the development of early memory impairment. The changes in buccal cell CK14 expression observed in this pilot study supports previous results suggesting the peripheral biomarkers and metabolic changes are not restricted to brain pathology alone in MCI and AD and could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD.

Clinical Benefits for Older Alzheimer's Disease Patients: Okayama Late Dementia Study (OLDS). - Matsuzono, Kosuke; Yamashita, Toru; Ohta, Yasuyuki; Hishikawa, Nozomi; Sato, Kota; Kono, Syoichiro; Deguchi, Kentaro; Nakano, Yumiko; Abe, Koji (J Alzheimers Dis, 2015)
BACKGROUND/OBJECTIVE: There are few reports on the effects of anti-Alzheimer's disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting. METHODS: "Okayama Late Dementia Study (OLDS)" is a retrospective clinical cohort study focusing on older AD patients (n = 373; age≥75 years) treated with monotherapy donepezil (n = 55), galantamine (n = 222), rivastigmine (n = 63), or memantine (n = 33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy. RESULTS: All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine ( *p <  0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months ( *p <  0.05), and memantine (3 and 6 months,  *p <  0.05) and rivastigmine (3 months,  **p <  0.01) improved Abe's Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months ( *p <  0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil ( *p <  0.05), as did female Geriatric Depression Scale scores at 6 months ( *p <  0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months ( *p <  0.05), while male ADL scores became worse with rivastigmine at 12 months ( *p <  0.05). CONCLUSION: OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.

Cognitive Effects of Soy Isoflavones in Patients with Alzheimer's Disease. - Gleason, Carey E; Fischer, Barbara L; Dowling, N Maritza; Setchell, Kenneth D R; Atwood, Craig S; Carlsson, Cynthia M; Asthana, Sanjay (J Alzheimers Dis, 2015)
BACKGROUND: In a previous trial, treatment with soy isoflavones was associated with improved nonverbal memory, construction abilities, verbal fluency, and speeded dexterity compared to treatment with placebo in cognitively healthy older adults. OBJECTIVE: The current trial aimed to examine the potential cognitive benefits of soy isoflavones in patients with Alzheimer's disease. METHODS: Sixty-five men and women over the age of 60 were treated with 100 mg/day soy isoflavones, or matching placebo capsules for six months. APOE genotype was determined for all participants. Cognitive outcomes and plasma isoflavone levels were measured at baseline, and at two additional time points: three and six months after baseline. RESULTS: Of the sixty-five participants enrolled, thirty-four (52.3% ) were women, and 31 (47.7% ) were APOEɛ4 positive. Average age was 76.3 (SD = 7.2) years. Fifty-nine (90.8% ) subjects completed all study visits. Plasma isoflavone levels increased in subjects treated with soy isoflavones compared to baseline and to placebo, although intersubject variability in plasma levels was large. No significant differences in treatment effects for cognition emerged between treatment groups or genders. Exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency. CONCLUSIONS: Six months of 100 mg/day treatment with soy isoflavones did not benefit cognition in older men and women with Alzheimer's disease. However, our results suggest the need to examine the role of isoflavone metabolism, i.e., the ability to effectively metabolize soy isoflavones by converting daidzen to equol when attempting to fully clarify the cognitive effects of isoflavones.

Cognitive Function and Its Relationship with Macular Pigment Optical Density and Serum Concentrations of its Constituent Carotenoids. - Kelly, David; Coen, Robert F; Akuffo, Kwadwo Owusu; Beatty, Stephen; Dennison, Jessica; Moran, Rachel; Stack, Jim; Howard, Alan N; Mulcahy, Riona; Nolan, John M (J Alzheimers Dis, 2015)
BACKGROUND: Macular pigment (MP) levels correlate with brain concentrations of lutein (L) and zeaxanthin (Z), and have also been shown to correlate with cognitive performance in the young and elderly. OBJECTIVE: To investigate the relationship between MP, serum concentrations of L and Z, and cognitive function in subjects free of retinal disease with low MP (Group 1, n = 105) and in subjects with AMD (Group 2, n = 121). METHODS: MP was measured using customized heterochromatic flicker photometry and dual-wavelength autofluorescence; cognitive function was assessed using a battery of validated cognition tests; serum L and Z concentrations were determined by HPLC. RESULTS: Significant correlations were evident between MP and various measures of cognitive function in both groups (r = -0.273 to 0.261, p≤0.05, for all). Both serum L and Z concentrations correlated significantly (r = 0.187, p≤0.05 and r = 0.197, p≤0.05, respectively) with semantic (animal) fluency cognitive scores in Group 2 (the AMD study group), while serum L concentrations also correlated significantly with Verbal Recognition Memory learning slope scores in the AMD study group (r = 0.200, p = 0.031). Most of the correlations with MP, but not serum L or Z, remained significant after controlling for age, gender, diet, and education level. CONCLUSION: MP offers potential as a non-invasive clinical biomarker of cognitive health, and appears more successful in this role than serum concentrations of L or Z.

Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer's Disease. - Liu-Seifert, Hong; Siemers, Eric; Price, Karen; Han, Baoguang; Selzler, Katherine J; Henley, David; Sundell, Karen; Aisen, Paul; Cummings, Jeffrey; Raskin, Joel; Mohs, Richard (J Alzheimers Dis, 2015)
BACKGROUND: The temporal relationship of cognitive deficit and functional impairment in Alzheimer's disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. OBJECTIVE: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. METHODS: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. RESULTS: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. CONCLUSIONS: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.

Comorbid Depression and Diabetes as a Risk for Mild Cognitive Impairment and Alzheimer's Disease in Elderly Mexican Americans. - Johnson, Leigh A; Gamboa, Adriana; Vintimilla, Raul; Cheatwood, Austin J; Grant, Alyann; Trivedi, Ashesh; Edwards, Melissa; Hall, James R; O'Bryant, Sid E (J Alzheimers Dis, 2015)
BACKGROUND: The links between diabetes, depression, and Alzheimer's disease (AD) has been established, but they are still poorly understood. However, little research has examined the effect that comorbidity of depression and diabetes has on cognitive impairment in an ethnically diverse sample. OBJECTIVE: The purpose of this study was to investigate the relationship between comorbid diabetes and depression on cognitive dysfunction; and examine the relationship in an ethnically diverse population. METHODS AND RESULTS: Analyses of data from 2,436 participants (914 men and 1,522 women) of three separate cohorts: HABLE, FRONTIER, and TARCC. In the HABLE cohort, comorbidity (odds ratio [OR] = 3.008; 95% CI = 1.358-6.667), age (OR = 1.138; 95% CI = 1.093-1.185), and education (OR = 0.915; 95% CI = 0.852-0.982) increased the risk of mild cognitive impairment (MCI) diagnosis among elderly Mexican American. In the TARCC cohort, results showed an increase risk of MCI in both non-Hispanic whites (OR = 18.795; 95% CI = 2.229-158.485) and Mexican Americans (OR = 8.417; 95% CI = 2.967-23.878). Finally, results in the FRONTIER cohort showed that in elderly Mexican Americans, comorbidity (OR = 2.754; 95% CI = 1.084-6.995) and age (OR = 1.069; 95% CI = 1.023-1.118) significantly increased risk of MCI. In non-Hispanic whites, comorbidity did not significantly increase risk of MCI. CONCLUSIONS: Among elderly Mexican Americans, comorbid depression and diabetes significantly increased risk for MCI and AD across cohorts. Effects of comorbid diabetes and depression on MCI were inconclusive. Our results support the link between comorbid diabetes and depression and risk for cognitive decline among Mexican Americans. This finding is of critical importance as the Hispanic population is at higher risk of developing AD.

Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults. - Nho, Kwangsik; Ramanan, Vijay K; Horgusluoglu, Emrin; Kim, Sungeun; Inlow, Mark H; Risacher, Shannon L; McDonald, Brenna C; Farlow, Martin R; Foroud, Tatiana M; Gao, Sujuan; Callahan, Christopher M; Hendrie, Hugh C; et al. (J Alzheimers Dis, 2015)
Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we PERFORMED genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.

The Continuing Failure of Bexarotene in Alzheimer's Disease Mice. - Balducci, Claudia; Paladini, Alessandra; Micotti, Edoardo; Tolomeo, Daniele; La Vitola, Pietro; Grigoli, Emanuele; Richardson, Jill C; Forloni, Gianluigi (J Alzheimers Dis, 2015)
Alzheimer's disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance. Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist, that increases ApoE expression and microglia phagocytosis and has been proposed as a promising therapy for AD, resolving both the amyloid pathology and memory loss. Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD. To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation. No differences were found when specifically investigating the microglial phagocytic state in vivo. In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice. These results suggest that BEXA has no beneficial effect on the multi-factorial pathologic phenotype of AD mice.

Correcting for the Absence of a Gold Standard Improves Diagnostic Accuracy of Biomarkers in Alzheimer's Disease. - Coart, Els; Barrado, Leandro García; Duits, Flora H; Scheltens, Philip; van der Flier, Wiesje M; Teunissen, Charlotte E; van der Vies, Saskia M; Burzykowski, Tomasz (J Alzheimers Dis, 2015)
BACKGROUND: Studies investigating the diagnostic accuracy of biomarkers for Alzheimer's disease (AD) are typically performed using the clinical diagnosis or amyloid-β positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers. OBJECTIVE: To determine the diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account. METHODS: To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers' true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-β1-42, Total tau, and P-tau181) by including the clinical diagnosis as imperfect reference test into the analysis. RESULTS: The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively. CONCLUSIONS: Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD.

Cortical Transcriptional Profiles in APOE4 Carriers with Alzheimer's Disease: Patterns of Protection and Degeneration. - Conejero-Goldberg, Concepcion; Hyde, Thomas M; Chen, Shufen; Herman, Mary M; Kleinman, Joel E; Davies, Peter; Goldberg, Terry E (J Alzheimers Dis, 2015)
Transcriptional profiling of postmortem Alzheimer's disease (AD) brain tissue has yielded important insights into disease. We recently described a novel approach to understand transcriptional changes in AD designed to identify both neurosusceptibility and intrinsic neuroprotective factors in young non-AD E4 carriers. Here we extend our work to APOE4-related AD itself. In temporal cortex (BA 21), a region known to be vulnerable to AD pathology, we identified over 1,400 transcripts that differed between APOE4 controls and APOE4 carriers diagnosed with AD. Results from somatosensory cortex (BA 1/2/3), a region relatively preserved in AD differed strikingly from temporal cortex in that differences were far fewer (37 versus 1,492). We also conducted another set of contrasts involving APOE3 AD cases and APOE4 AD cases to better understand what transcriptional differences were dependent on genotype, but independent of disease status. When analyzing interregional differences, ten pathways differed between both brain areas in the APOE4 AD cases to APOE4 controls contrast and two pathways differed between both brain areas in the APOE4 cases to APOE3 controls contrast. Base excision repair pathway was found in common for both contrasts. In summary, our results indicate that many of the molecular changes identified in the brains of patients with AD reflect the non-specific consequences of neurodegeneration, rather than causative processes. Additionally, the molecular signatures specific to somatosensory cortex may make it uniquely resistant to AD pathology and thereby could provide important leads for treatment.

A Critical Proton MR Spectroscopy Marker of Alzheimer's Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ɛ4 Mexico City Children and Their Parents. - Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Sánchez, Gastón Melo; Rodríguez-Díaz, Joel; Torres-Jardón, Ricardo; Styner, Martin; Mukherjee, Partha S; Lin, Weili; Jewells, Valerie (J Alzheimers Dis, 2015)
Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer's disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly different between cohorts (p = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ɛ4 MC children and in left hippocampus in MC APOE ɛ4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ɛ4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority.

Depression and Suicidal Ideation During Two Psychosocial Treatments in Older Adults with Major Depression and Dementia. - Kiosses, Dimitris N; Rosenberg, Paul B; McGovern, Amanda; Fonzetti, Pasquale; Zaydens, Hana; Alexopoulos, George S (J Alzheimers Dis, 2015)
BACKGROUND: Depression is prevalent in dementia and contributes to poor outcomes for patients and their families. Antidepressants have limited efficacy in older adults with major depression and dementia, and psychosocial interventions are under-investigated. OBJECTIVE: To examine the course, predictors and moderators of depression and suicidal ideation during 12 weeks of home-delivered Problem Adaptation Therapy (PATH) versus Supportive Therapy for Cognitively Impaired Older Adults (ST-CI) in 39 older adults with major depression and dementia. METHODS: Thirty-nine older adults with major depression, mild or moderate dementia, and disability participated in a randomized controlled trial that compared the efficacy of PATH versus ST-CI. Depression and suicidal ideation were assessed with Cornell Scale for Depression in Dementia Total Score and Suicide Item. RESULTS: PATH participants had significantly greater reduction in depression than ST-CI participants over 12 weeks of treatment. PATH participants with high social support had the greatest reduction in depression. Both treatments had comparable reduction in suicidal ideation. CONCLUSION: PATH is more effective in reducing depression in older adults with major depression and dementia compared to ST-CI. These results are clinically significant as antidepressants have limited efficacy in this population. Home-delivered psychosocial treatments may reduce suicidal ideation in this population.

Depressive Symptoms and Biomarkers of Alzheimer's Disease in Cognitively Normal Older Adults. - Donovan, Nancy J; Hsu, David C; Dagley, Alexander S; Schultz, Aaron P; Amariglio, Rebecca E; Mormino, Elizabeth C; Okereke, Olivia I; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A (J Alzheimers Dis, 2015)
Even low levels of depressive symptoms are associated with an increased risk of cognitive decline in older adults without overt cognitive impairment (CN). Our objective was to examine whether very low, "subthreshold symptoms of depression" are associated with Alzheimer's disease (AD) biomarkers of neurodegeneration in CN adults and whether these associations are specific to particular depressive symptoms. We analyzed data from 248 community-dwelling CN older adults, including measurements of cortical amyloid burden, neurodegeneration markers of hippocampal volume (HV) and cerebral 18F-fluorodeoxyglucose (FDG) metabolism in a composite of AD-related regions and the 30-item Geriatric Depression Scale (GDS). Participants with GDS >10 were excluded. General linear regression models evaluated the cross-sectional relations of GDS to HV or FDG in separate backward elimination models. Predictors included GDS total score, age, gender, premorbid intelligence, a binary amyloid variable and its interaction with GDS. Principal component analyses of GDS item scores revealed three factors (the Dysphoria, Apathy-Anhedonia, and Anxiety-Concentration Factors). In secondary analyses, GDS total score was replaced with the three factor scores in repeated models. Higher GDS score (p = 0.03) was significantly associated with lower HV and was marginally related (p = 0.06) to FDG hypometabolism. In secondary models, higher Dysphoria (p = 0.02) and Apathy-Anhedonia (p = 0.05) were related to lower HV while higher Apathy-Anhedonia (p = 0.003) was the sole factor related to FDG hypometabolism. Amyloid was not a significant predictor in any model. In conclusion, very low-level dysphoria, apathy and anhedonia may point to neurodegeneration in AD-related regions but this association appears to be independent of amyloid burden.

Diabetes is Associated with Worse Executive Function in Both Eastern and Western Populations: Shanghai Aging Study and Mayo Clinic Study of Aging. - Zhao, Qianhua; Roberts, Rosebud O; Ding, Ding; Cha, Ruth; Guo, Qihao; Meng, Haijiao; Luo, Jianfeng; Machulda, Mary M; Shane Pankratz, V; Wang, Bei; Christianson, Teresa J H; Aakre, Jeremiah A; et al. (J Alzheimers Dis, 2015)
BACKGROUND AND OBJECTIVES: It remains unknown whether the association between diabetes mellitus (DM) and cognitive function differs in Eastern and Western populations. This study aimed to elucidate whether DM is associated with worse cognitive performance in both populations. METHODS: The Shanghai Aging Study (SAS) and the Mayo Clinic Study of Aging (MCSA) are two population-based studies with similar design and methodology in Shanghai, China and Rochester, MN, USA. Non-demented participants underwent cognitive testing, and DM was assessed from the medical record. Separate analyses were performed in SAS and MCSA regarding the association between DM and cognitive performance. RESULTS: A total of 3,348 Chinese participants in the SAS and 3,734 American subjects in the MCSA were included. Compared with MCSA subjects, SAS participants were younger, less educated, and had lower frequency of vascular disease, APOE ɛ4 carriers and obesity. Participants with DM (compared to non-DM participants) performed significantly worse on all the cognitive domains in both the SAS and MCSA. After adjustment for age, gender, education, and vascular covariates, DM was associated with worse performance in executive function (β=-0.15, p = 0.001 for SAS, and β=-0.10, p = 0.008 for MCSA) in the total sample and in the cognitively normal sub-sample. Furthermore, DM was associated with poor performance in visuospatial skills, language, and memory in the SAS, but not in the MCSA. CONCLUSIONS: Diabetes is associated with cognitive dysfunction and, in particular, exerts a negative impact on executive function regardless of race, age, and prevalence of vascular risk factors.

Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ɛ4 Carriers and Adults with Mild Cognitive Impairment. - Hanson, Angela J; Bayer, Jennifer L; Baker, Laura D; Cholerton, Brenna; VanFossen, Brian; Trittschuh, Emily; Rissman, Robert A; Donohue, Michael C; Moghadam, Setareh H; Plymate, Stephen R; Craft, Suzanne (J Alzheimers Dis, 2015)
BACKGROUND: High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimer's disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions. OBJECTIVE: To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor. METHODS: 46 adults with either cognitive impairment (CI) or normal cognition (NC) ingested a LOW (25% total fat, 7% SF, GI <55) and a HIGH meal (50% total fat, 25% SF, GI >70) in a blinded random fashion. Participants then underwent cognitive testing and blood sampling for metabolic and Alzheimer's disease biomarkers. Data were analyzed using repeated measures ANOVA and Spearman correlations. RESULTS: E4-adults with NC demonstrated lower delayed memory scores after the HIGH compared to the LOW meal, whereas normal E4+ and CI E4- groups had higher scores after the HIGH meal (ANOVA p = 0.03). These findings were associated with meal-induced changes in glucose (p = 0.05), insulin (p = 0.004), triglycerides (p <  0.01), and plasma Aβ42 (p = 0.05). CONCLUSIONS: These preliminary data suggest that cognitive performance of adults without CI may worsen following high SF and sugar meals, whereas adults with CI or those at risk for CI due to E4 status may benefit acutely from such meals. Furthermore, plasma Aβ was affected by meal type, suggesting a relationship between metabolic response and amyloid regulation.

Divalent Copper as a Major Triggering Agent in Alzheimer's Disease. - Brewer, George J (J Alzheimers Dis, 2015)
Alzheimer's disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper. Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates. An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.

The Existence of Primary Age-Related Tauopathy Suggests that not all the Cases with Early Braak Stages of Neurofibrillary Pathology are Alzheimer's Disease. - Giaccone, Giorgio (J Alzheimers Dis, 2015)
The distinction between Alzheimer's disease (AD) and Primary Age-Related Tauopathy (PART) is a hotly debated issue. As most lines of evidence support the tenet that tau pathology occurs downstream of amyloid-β deposition, it seems reasonable to consider PART as a separate disease process not necessarily related to Aβ and hence AD. Following this view, the early stages of neurofibrillary pathology may not always be the forerunner of diffuse neurofibrillary changes and AD. The ongoing debate further enhances the need for greater caution against any future predictions using tau cerebrospinal fluid and imaging biomarkers.

The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease. - Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Niehoff, Michael L; Morley, John E; Jelsing, Jacob; Pyke, Charles; Bjerre Knudsen, Lotte; Farr, Susan A; Vrang, Niels (J Alzheimers Dis, 2015)
Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by Aβ plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of Aβ plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD.

Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer's Disease Prevention and Early Intervention. - Keeney, Jeriel Thomas-Richard; Ibrahimi, Shaher; Zhao, Liqin (J Alzheimers Dis, 2015)
Three major genetic isoforms of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4, exist in humans and lead to differences in susceptibility to Alzheimer's disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-β (Aβ) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2, ApoE3, and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aβ dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention.

Identification of Novel Tau Interactions with Endoplasmic Reticulum Proteins in Alzheimer's Disease Brain. - Meier, Shelby; Bell, Michelle; Lyons, Danielle N; Ingram, Alexandria; Chen, Jing; Gensel, John C; Zhu, Haining; Nelson, Peter T; Abisambra, Jose F (J Alzheimers Dis, 2015)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the formation of extracellular amyloid plaques and intraneuronal tau tangles. We recently identified that tau associates with proteins known to participate in endoplasmic reticulum (ER)-associated degradation (ERAD); consequently, ERAD becomes dysfunctional and causes neurotoxicity. We hypothesized that tau associates with other ER proteins, and that this association could also lead to cellular dysfunction in AD. Portions of human AD and non-demented age matched control brains were fractionated to obtain microsomes, from which tau was co-immunoprecipitated. Samples from both conditions containing tau and its associated proteins were analyzed by mass spectrometry. In total, we identified 91 ER proteins that co-immunoprecipitated with tau; 15.4% were common between AD and control brains, and 42.9% only in the AD samples. The remainder, 41.8% of the proteins, was only seen in the control brain samples. We identified a variety of previously unreported interactions between tau and ER proteins. These proteins participate in over sixteen functional categories, the most abundant being involved in RNA translation. We then determined that association of tau with these ER proteins was different between the AD and control samples. We found that tau associated equally with the ribosomal protein L28 but more robustly with the ribosomal protein P0. These data suggest that the differential association between tau and ER proteins in disease could reveal the pathogenic processes by which tau induces cellular dysfunction.

Impairment of Age Estimation from Faces in Alzheimer's Disease. - Moyse, Evelyne; Bastin, Christine; Salmon, Eric; Brédart, Serge (J Alzheimers Dis, 2015)
A prerequisite for any function in social cognition is the perception and processing of social cues. Age estimation is a skill that is used in everyday life and is fundamental in social interactions. This study evaluated whether facial age estimation is impaired in patients with mild to moderate Alzheimer's disease (AD). The current age of faces is known to have an impact on age estimation, and therefore stimuli belonging to different age groups (young, middle-aged, and older adults' faces) were used. As expected, an impairment of age estimation from faces was observed in mild to moderate AD patients. However, the profile of impairment depended on the age of faces and stage of the disease. Mild AD patients presented difficulties mainly in assessing the age of middle-aged adults. In moderate disease stage, these difficulties also affected the age estimation of young adult faces. Interestingly, AD patients remained relatively good at estimating the age of older adults' faces, compared to healthy controls.

Long-Term Interrelationship between Brain Metabolism and Amyloid Deposition in Mild Cognitive Impairment. - Kemppainen, Nina; Joutsa, Juho; Johansson, Jarkko; Scheinin, Noora M; Någren, Kjell; Rokka, Johanna; Parkkola, Riitta; Rinne, Juha O (J Alzheimers Dis, 2015)
The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.

Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease. - Migliaccio, Raffaella; Agosta, Federica; Possin, Katherine L; Canu, Elisa; Filippi, Massimo; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Gorno-Tempini, Maria Luisa (J Alzheimers Dis, 2015)
The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate.

The Multi-Target Drug M30 Shows Pro-Cognitive and Anti-Inflammatory Effects in a Rat Model of Alzheimer's Disease. - Pimentel, Luisa S; Allard, Simon; Do Carmo, Sonia; Weinreb, Orly; Danik, Marc; Hanzel, Cecilia E; Youdim, Moussa B; Cuello, A Claudio (J Alzheimers Dis, 2015)
Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.

A Novel Plasma Based Biomarker of Alzheimer's Disease. - Bradley-Whitman, Melissa A; Abner, Erin; Lynn, Bert C; Lovell, Mark A (J Alzheimers Dis, 2015)
Specific biomarkers in a readily accessible biological fluid, such as blood, could aid in the identification, characterization, validation, and routine monitoring of Alzheimer's disease (AD) progression. In the current study, levels of the previously described novel cerebrospinal fluid aberrant protein complex composed of prostaglandin-D-synthase (PDS) and transthyretin (TTR) were quantified in plasma by a custom two-probe sandwich ELISA and compared to amyloid-β (Aβ)1-42 as a standard plasma biomarker of AD. Plasma was analyzed from 140 probable AD subjects, 135 subjects with mild cognitive impairment (MCI), 74 normal control subjects (NC) prior to MCI transition, 23 diseased control (DC) subjects with either frontotemporal dementia or dementia with Lewy bodies, and 182 normal control (NC) subjects who did not progress to MCI or dementia. Levels of Aβ 1-42 were significantly elevated in NC subjects prior to MCI conversion but significantly reduced in probable AD subjects compared to NC subjects. Similarly, levels of the PDS-TTR complex were significantly reduced in both MCI and probable AD subjects compared to NC subjects. Furthermore, levels of Aβ 1-42 and the PDS-TTR complex were not significantly different in DC subjects compared to NC subjects. MMSE scores were weakly but significantly correlated with plasma levels of the PDS-TTR complex and Aβ 1-42. Trail B scores were weakly but significantly correlated with plasma levels of Aβ 1-42. Comparison of receiver operating curves shows the PDS-TTR complex is comparable to Aβ 1-42 in both MCI and probable AD subjects.

Olfactory Dysfunction in ApoE ε4/4 Homozygotes with Alzheimer's Disease. - Oleson, Stephanie; Murphy, Claire (J Alzheimers Dis, 2015)
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory impairment and the presence of amyloid plaques and neurofibrillary tangles. The associated neuropathology originates in brain areas responsible for olfaction, which makes olfactory tasks potentially useful for assessing AD. The strongest genetic risk factor for AD is the apolipoprotein E (ApoE) ε4 allele that has been associated with increased cognitive and olfactory deficits. While individuals carrying one ε4 allele of the ApoE gene are at increased risk for AD relative to non-carriers, those with two copies of the ε4 allele demonstrate an even higher risk for developing AD. Furthermore, homozygous ApoE ε4/4 individuals diagnosed with AD are known to have heightened amyloid burden and a more rapid rate of cognitive decline relative to heterozygous ε3/4 ApoE carriers. All of these factors suggest there are differences in severity and progression of AD as a function of possessing one versus two ε4 alleles. The current study investigated olfactory functioning in homozygous ε4/4 older adults diagnosed with probable AD. Compared to demographically matched ε3/3 and ε3/4 individuals, ε4/4 individuals showed deficits in odor identification and remote odor memory as measured by odor familiarity ratings. The current findings suggest that these particular domains of olfactory functioning may be more impaired in AD ε4/4 homozygotes compared to ε3/4 heterozygotes and ε3/3 homozygotes. These deficits give insight into how the presence of two ε4 alleles may differentially affect the progression of AD and suggest the usefulness of odor tasks in detecting those at risk for AD.

A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer's Disease. - Remington, Ruth; Bechtel, Cynthia; Larsen, David; Samar, Annemarie; Doshanjh, Laura; Fishman, Paul; Luo, Yuan; Smyers, Kathleen; Page, Robert; Morrell, Christopher; Shea, Thomas B (J Alzheimers Dis, 2015)
Background: Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer's disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention. Objective: We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD. Methods: A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer's Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. Results: The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort. Conclusions: These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior.

Reduced Benefit of Memory Elaboration in Older Adults with Subjective Memory Decline. - Pike, Kerryn E; Zeneli, Amina; Ong, Ben; Price, Sarah; Kinsella, Glynda J (J Alzheimers Dis, 2015)
BACKGROUND: Cognitive interventions for neurodegenerative diseases, such as Alzheimer's disease (AD), are best targeted at the preclinical stages, and subjective memory decline (SMD) without objective memory impairment on standard tests in older adults may represent a very early preclinical stage. Elaborated encoding effectively enhances memory performance for healthy older adults (HOAs), but has not been examined in people with SMD. OBJECTIVE: To examine elaborated encoding in people with SMD, compared with HOAs. METHODS: Participants were 32 HOAs and 22 people with SMD, defined using the Memory Complaint Questionnaire. Participants completed a verbal paired associate learning (PAL) task with delayed recall under elaborated and non-elaborated encoding conditions, as well as the California Verbal Learning Test-II. RESULTS: On the PAL learning trials, with age controlled, a significant interaction of group X encoding condition emerged, F(1, 51) =  6.47, MSE = 6.54, p = 0.014, ηp2 = 0.11. Simple main effects revealed no differences between groups in the non-elaborated condition, but in the elaborated condition HOAs recalled more pairs than SMD, although both groups benefited from elaboration. At delayed recall, HOA recalled more pairs than SMD, F(1, 51) =  4.59, p = 0.037, ηp2 = 0.08, and both groups benefited from elaboration, F(1, 52) =  19.25, p <  0.001, ηp2 = 0.27. CONCLUSION: People with SMD benefit from elaborated encoding, although not to the same extent as HOAs. This objective difference in complex learning and memory suggests neural changes in SMD that may represent preclinical AD. Elaborated encoding is a promising technique to help maintain memory and decrease anxiety in this at-risk population.

sAβPPα is a Potent Endogenous Inhibitor of BACE1. - Peters-Libeu, Clare; Campagna, Jesus; Mitsumori, Michael; Poksay, Karen S; Spilman, Patricia; Sabogal, Alex; Bredesen, Dale E; John, Varghese (J Alzheimers Dis, 2015)
Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-β peptide (Aβ), and as such has been a major target of Alzheimer's disease (AD) drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and in traumatic brain injury, and is also associated with stroke due to cerebral amyloid angiopathy. Herein we report for the first time that sAβPPα, the product of the cleavage of AβPP by α-secretase, is a potent endogenous direct inhibitor of the BACE enzyme, and that its inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering, we show that sAβPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sAβPPα and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAβPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAβPPα as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of Aβ.

Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer's Disease. - Edmonds, Emily C; Delano-Wood, Lisa; Galasko, Douglas R; Salmon, David P; Bondi, Mark W (J Alzheimers Dis, 2015)
The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.

Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment. - Malpas, Charles B; Saling, Michael M; Velakoulis, Dennis; Desmond, Patricia; O'Brien, Terence J (J Alzheimers Dis, 2015)
Alzheimer's disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials.

Tracking Discourse Complexity Preceding Alzheimer's Disease Diagnosis: A Case Study Comparing the Press Conferences of Presidents Ronald Reagan and George Herbert Walker Bush. - Berisha, Visar; Wang, Shuai; LaCross, Amy; Liss, Julie (J Alzheimers Dis, 2015)
Changes in some lexical features of language have been associated with the onset and progression of Alzheimer's disease. Here we describe a method to extract key features from discourse transcripts, which we evaluated on non-scripted news conferences from President Ronald Reagan, who was diagnosed with Alzheimer's disease in 1994, and President George Herbert Walker Bush, who has no known diagnosis of Alzheimer's disease. Key word counts previously associated with cognitive decline in Alzheimer's disease were extracted and regression analyses were conducted. President Reagan showed a significant reduction in the number of unique words over time and a significant increase in conversational fillers and non-specific nouns over time. There was no significant trend in these features for President Bush.

Variants in Antiviral Genes are Risk Factors for Cognitive Decline and Dementia. - Licastro, Federico; Raschi, Elena; Carbone, Ilaria; Porcellini, Elisa (J Alzheimers Dis, 2015)
A gene association study of factors regulating antiviral response such as interferon (IFN)-λ3, also known as IL-28B, mediator complex (Med) 23, and interferon regulatory factor (IRF) 7 with cognitive deterioration and Alzheimer's disease (AD) was performed. Differences in the TT genotype distribution of IL-28B single nucleotide polymorphism (SNP) between AD patients and controls were found. The GG genotype of Med23 gene appeared to influence the progression of the disease, being more frequent in the APOE ε4 negative elderly that developed AD during the five year follow-up. Leukocyte positivity for Epstein Barr virus (EBV) and human herpes virus (HHV)-6 DNA was analyzed. Med23 GG genotype correlated with the positivity to HHV-6 DNA. EBV and HHV-6 plasma IgG levels were also investigated and EBV IgG levels were increased in AD with the IRF7 GG genotype. A differential genetic background in genes regulating anti-virus responses was associated with an increased risk of cognitive decline and AD. EBV and HHV-6 appeared to be risk factors for AD in genetically susceptible elderly.

Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. - Dubois, Bruno; Feldman, Howard H; Jacova, Claudia; Hampel, Harald; Molinuevo, José Luis; Blennow, Kaj; DeKosky, Steven T; Gauthier, Serge; Selkoe, Dennis; Bateman, Randall; Cappa, Stefano; Crutch, Sebastian; et al. (Lancet Neurol, 2014)
In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
Keywords: Alzheimer Disease; Biomarkers; Humans; International Cooperation; Phenotype; Practice Guidelines as Topic; Societies, Medical

C9orf72 nucleotide repeat structures initiate molecular cascades of disease. - Haeusler, Aaron R; Donnelly, Christopher J; Periz, Goran; Simko, Eric A J; Shaw, Patrick G; Kim, Min-Sik; Maragakis, Nicholas J; Troncoso, Juan C; Pandey, Akhilesh; Sattler, Rita; Rothstein, Jeffrey D; Wang, Jiou (Nature, 2014)
A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
Keywords: Amyotrophic Lateral Sclerosis; B-Lymphocytes; Base Sequence; Cell Nucleolus; DNA; DNA Repeat Expansion; Frontotemporal Dementia; G-Quadruplexes; HEK293 Cells; Humans; Models, Molecular; Neurons; Open Reading Frames; Phosphoproteins; Ribonucleoproteins; RNA; RNA-Binding Proteins; Stress, Physiological; Transcription, Genetic

Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. - Doody, Rachelle S; Thomas, Ronald G; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; Raman, Rema; Sun, Xiaoying; Aisen, Paul S; Siemers, Eric; Liu-Seifert, Hong; et al. (N Engl J Med, 2014)
BACKGROUND: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. METHODS: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease. RESULTS: Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49). CONCLUSIONS: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal, Humanized; Apolipoproteins E; Biomarkers; Cognition; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Neuropsychological Tests; Severity of Illness Index; tau Proteins; Treatment Failure

Plasma phospholipids identify antecedent memory impairment in older adults. - Mapstone, Mark; Cheema, Amrita K; Fiandaca, Massimo S; Zhong, Xiaogang; Mhyre, Timothy R; MacArthur, Linda H; Hall, William J; Fisher, Susan G; Peterson, Derick R; Haley, James M; Nazar, Michael D; Rich, Steven A; et al. (Nat Med, 2014)
Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.
Keywords: Aged; Alzheimer Disease; Asparagine; Biomarkers; Carnitine; Cohort Studies; Dipeptides; Female; Humans; Longitudinal Studies; Lysophosphatidylcholines; Malates; Male; Memory Disorders; Metabolome; Mild Cognitive Impairment; Neuropsychological Tests; Phosphatidylcholines; Phosphatidylinositols; Phospholipids; Proline; Prospective Studies; Sensitivity and Specificity; Sphingomyelins; Ursodeoxycholic Acid

REST and stress resistance in ageing and Alzheimer's disease. - Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Chen, Yiwen; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Liu, X Shirley; Bennett, David A; Colaiácovo, Monica P; et al. (Nature, 2014)
Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Autophagy; Brain; Caenorhabditis elegans Proteins; Cell Death; Cell Nucleus; Chromatin Immunoprecipitation; Cognition; DNA-Binding Proteins; Down-Regulation; Frontotemporal Dementia; Gene Expression Regulation; Humans; Lewy Body Disease; Longevity; Mice; Mild Cognitive Impairment; Neurons; Neuroprotective Agents; Oxidative Stress; Phagosomes; Repressor Proteins; Transcription Factors; Up-Regulation; Wnt Signaling Pathway; Young Adult

Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. - Rebok, George W; Ball, Karlene; Guey, Lin T; Jones, Richard N; Kim, Hae-Young; King, Jonathan W; Marsiske, Michael; Morris, John N; Tennstedt, Sharon L; Unverzagt, Frederick W; Willis, Sherry L (J Am Geriatr Soc, 2014)
OBJECTIVES: To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years. DESIGN: Ten-year follow-up of a randomized, controlled single-blind trial (Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)) with three intervention groups and a no-contact control group. SETTING: Six U.S. cities. PARTICIPANTS: A volunteer sample of 2,832 persons (mean baseline age 73.6; 26% African American) living independently. INTERVENTION: Ten training sessions for memory, reasoning, or speed of processing; four sessions of booster training 11 and 35 months after initial training. MEASUREMENTS: Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function. RESULTS: Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADLs) (memory: effect size = 0.48, 99% confidence interval (CI) = 0.12-0.84; reasoning: effect size = 0.38, 99% CI = 0.02-0.74; speed of processing: effect size = 0.36, 99% CI = 0.01-0.72). At a mean age of 82, approximately 60% of trained participants, versus 50% of controls (P < .05), were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size = 0.23, 99% CI = 0.09-0.38; speed of processing: effect size = 0.66, 99% CI = 0.43-0.88). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size = 0.21, 99% CI = 0.01-0.41) and the speed-of-processing intervention for speed-of-processing performance (effect size = 0.62, 99% CI = 0.31-0.93). CONCLUSION: Each Advanced Cognitive Training for Independent and Vital Elderly cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Aging; Cognition Disorders; Cognitive Therapy; Female; Follow-Up Studies; Humans; Independent Living; Male; Memory Disorders; Mental Processes; Single-Blind Method; United States

A three-dimensional human neural cell culture model of Alzheimer's disease. - Choi, Se Hoon; Kim, Young Hye; Hebisch, Matthias; Sliwinski, Christopher; Lee, Seungkyu; D'Avanzo, Carla; Chen, Hechao; Hooli, Basavaraj; Asselin, Caroline; Muffat, Julien; Klee, Justin B; Zhang, Can; et al. (Nature, 2014)
Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Cell Culture Techniques; Cell Differentiation; Drug Evaluation, Preclinical; Extracellular Space; Glycogen Synthase Kinase 3; Humans; Microtubule-Associated Proteins; Models, Biological; Neural Stem Cells; Neurites; Phosphorylation; Presenilin-1; Protein Aggregation, Pathological; Reproducibility of Results; tau Proteins

Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. - Salloway, Stephen; Sperling, Reisa; Fox, Nick C; Blennow, Kaj; Klunk, William; Raskind, Murray; Sabbagh, Marwan; Honig, Lawrence S; Porsteinsson, Anton P; Ferris, Steven; Reichert, Marcel; Ketter, Nzeera; et al. (N Engl J Med, 2014)
BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal, Humanized; Apolipoproteins E; Biomarkers; Brain; Cognition; Double-Blind Method; Edema; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Neuropsychological Tests; Phosphorylation; Positron-Emission Tomography; Severity of Illness Index; tau Proteins; Treatment Failure

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. - Villeda, Saul A; Plambeck, Kristopher E; Middeldorp, Jinte; Castellano, Joseph M; Mosher, Kira I; Luo, Jian; Smith, Lucas K; Bieri, Gregor; Lin, Karin; Berdnik, Daniela; Wabl, Rafael; Udeochu, Joe; et al. (Nat Med, 2014)
As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
Keywords: Age Factors; Aging; Animals; Blood Transfusion; Blotting, Western; Cell Line; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; DNA Primers; Hippocampus; Immunohistochemistry; Mice; Mice, Inbred C57BL; Microarray Analysis; Neuronal Plasticity; Parabiosis; Polymerase Chain Reaction

Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. - Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R; Lesinski, Andrea N; Asselin, Caroline N; Mullin, Kristina; Hooli, Basavaraj; Choi, Se Hoon; Hyman, Bradley T; Tanzi, Rudolph E (Neuron, 2013)
The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Case-Control Studies; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Matched-Pair Analysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia; Polymorphism, Single Nucleotide; Reference Values; RNA, Messenger; Sialic Acid Binding Ig-like Lectin 3

Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies. - Piazza, Fabrizio; Greenberg, Steven M; Savoiardo, Mario; Gardinetti, Margherita; Chiapparini, Luisa; Raicher, Irina; Nitrini, Ricardo; Sakaguchi, Hideya; Brioschi, Monica; Billo, Giuseppe; Colombo, Antonio; Lanzani, Francesca; et al. (Ann Neurol, 2013)
OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri. METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated. RESULTS: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel. INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.
Keywords: Adult; Aged; Amyloid beta-Peptides; Apolipoproteins E; Autoantibodies; Brain; Case-Control Studies; Cerebral Amyloid Angiopathy; Female; Humans; Inflammation; Male; Middle Aged; Peptide Fragments; Phosphorylation; Retrospective Studies; Steroids; tau Proteins

Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. - Zhang, Bin; Gaiteri, Chris; Bodea, Liviu-Gabriel; Wang, Zhi; McElwee, Joshua; Podtelezhnikov, Alexei A; Zhang, Chunsheng; Xie, Tao; Tran, Linh; Dobrin, Radu; Fluder, Eugene; Clurman, Bruce; et al. (Cell, 2013)
The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
Keywords: Adaptor Proteins, Signal Transducing; Alzheimer Disease; Animals; Bayes Theorem; Brain; Gene Regulatory Networks; Humans; Membrane Proteins; Mice; Microglia

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. - Lambert, J C; Ibrahim-Verbaas, C A; Harold, D; Naj, A C; Sims, R; Bellenguez, C; DeStafano, A L; Bis, J C; Beecham, G W; Grenier-Boley, B; Russo, G; Thorton-Wells, T A; et al. (Nat Genet, 2013)
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Keywords: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cohort Studies; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. - Kondo, Takayuki; Asai, Masashi; Tsukita, Kayoko; Kutoku, Yumiko; Ohsawa, Yutaka; Sunada, Yoshihide; Imamura, Keiko; Egawa, Naohiro; Yahata, Naoki; Okita, Keisuke; Takahashi, Kazutoshi; Asaka, Isao; et al. (Cell Stem Cell, 2013)
Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Cell Differentiation; Cerebral Cortex; Docosahexaenoic Acids; Humans; Induced Pluripotent Stem Cells; Intracellular Space; Models, Biological; Mutant Proteins; Neurons; Oxidative Stress; Phenotype; Protein Structure, Quaternary

Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. - Jack, Clifford R; Knopman, David S; Jagust, William J; Petersen, Ronald C; Weiner, Michael W; Aisen, Paul S; Shaw, Leslie M; Vemuri, Prashanthi; Wiste, Heather J; Weigand, Stephen D; Lesnick, Timothy G; Pankratz, Vernon S; et al. (Lancet Neurol, 2013)
In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Humans; Models, Biological; Nonlinear Dynamics; tau Proteins

TREM2 variants in Alzheimer's disease. - Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S K; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; et al. (N Engl J Med, 2013)
BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).
Keywords: Aged; Alzheimer Disease; Animals; Brain; Exome; Genetic Variation; Genome-Wide Association Study; Genotype; Genotyping Techniques; Heterozygote; Humans; Membrane Glycoproteins; Mice; Mice, Inbred A; Mutation; Receptors, Immunologic; Risk Factors; RNA, Messenger; Sequence Analysis, DNA

Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. - Buchhave, Peder; Minthon, Lennart; Zetterberg, Henrik; Wallin, Asa K; Blennow, Kaj; Hansson, Oskar (Arch Gen Psychiatry, 2012)
CONTEXT: Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease. OBJECTIVES: To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD. DESIGN: A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years). SETTING: Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. MAIN OUTCOME MEASURE Conversion to AD dementia. RESULTS: During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%. CONCLUSIONS: Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Follow-Up Studies; Humans; Male; Mild Cognitive Impairment; Peptide Fragments; Predictive Value of Tests; tau Proteins; Time Factors

Cognitive reserve in ageing and Alzheimer's disease. - Stern, Yaakov (Lancet Neurol, 2012)
The concept of cognitive reserve provides an explanation for differences between individuals in susceptibility to age-related brain changes or pathology related to Alzheimer's disease, whereby some people can tolerate more of these changes than others and maintain function. Epidemiological studies suggest that lifelong experiences, including educational and occupational attainment, and leisure activities in later life, can increase this reserve. For example, the risk of developing Alzheimer's disease is reduced in individuals with higher educational or occupational attainment. Reserve can conveniently be divided into two types: brain reserve, which refers to differences in the brain structure that may increase tolerance to pathology, and cognitive reserve, which refers to differences between individuals in how tasks are performed that might enable some people to be more resilient to brain changes than others. Greater understanding of the concept of cognitive reserve could lead to interventions to slow cognitive ageing or reduce the risk of dementia.
Keywords: Aging; Alzheimer Disease; Animals; Cognitive Reserve; Humans

Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. - Talbot, Konrad; Wang, Hoau-Yan; Kazi, Hala; Han, Li-Ying; Bakshi, Kalindi P; Stucky, Andres; Fuino, Robert L; Kawaguchi, Krista R; Samoyedny, Andrew J; Wilson, Robert S; Arvanitakis, Zoe; Schneider, Julie A; et al. (J Clin Invest, 2012)
While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Brain; Cerebellar Cortex; Cognition Disorders; Diabetes Complications; Drug Resistance; Female; Glucose; Hippocampus; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Like Growth Factor I; Male; Middle Aged; Phosphorylation; Phosphoserine; Protein Processing, Post-Translational; Recombinant Proteins; Signal Transduction

An epigenetic blockade of cognitive functions in the neurodegenerating brain. - Gräff, Johannes; Rei, Damien; Guan, Ji-Song; Wang, Wen-Yuan; Seo, Jinsoo; Hennig, Krista M; Nieland, Thomas J F; Fass, Daniel M; Kao, Patricia F; Kahn, Martin; Su, Susan C; Samiei, Alireza; et al. (Nature, 2012)
Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
Keywords: Acetylation; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Epigenesis, Genetic; Gene Expression Regulation; Gene Knockdown Techniques; Hippocampus; Histone Deacetylase 2; Histones; Humans; Hydrogen Peroxide; Memory Disorders; Mice; Neurodegenerative Diseases; Neuronal Plasticity; Peptide Fragments; Phosphorylation; Promoter Regions, Genetic; Receptors, Glucocorticoid; RNA Polymerase II

Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. - Head, Denise; Bugg, Julie M; Goate, Alison M; Fagan, Anne M; Mintun, Mark A; Benzinger, Tammie; Holtzman, David M; Morris, John C (Arch Neurol, 2012)
OBJECTIVE: APOE ε4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults. DESIGN: APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association. SETTING: Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri. PARTICIPANTS: A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer's Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants. RESULTS: APOE ε4 carriers evidenced higher [(11)C]PiB binding (P<.001) and lower CSF Aβ42 levels (P<.001) than did noncarriers. Our previous findings of higher [(11)C]PiB binding (P=.005) and lower CSF Aβ42 levels (P=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [(11)C]PiB binding (P=.008) such that a more sedentary lifestyle was significantly associated with higher [(11)C]PiB binding for ε4 carriers (P=.013) but not for noncarriers (P=.20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments. CONCLUSION: Collectively, these results suggest that cognitively normal sedentary APOE ε4-positive individuals may be at augmented risk for cerebral amyloid deposition.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Cognition; Cohort Studies; Exercise; Female; Genetic Association Studies; Genotype; Humans; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Regression Analysis; Surveys and Questionnaires; Thiazoles

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. - Jonsson, Thorlakur; Atwal, Jasvinder K; Steinberg, Stacy; Snaedal, Jon; Jonsson, Palmi V; Bjornsson, Sigurbjorn; Stefansson, Hreinn; Sulem, Patrick; Gudbjartsson, Daniel; Maloney, Janice; Hoyte, Kwame; Gustafson, Amy; et al. (Nature, 2012)
The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.
Keywords: Aging; Alleles; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cognition; Cognition Disorders; Genetic Predisposition to Disease; HEK293 Cells; Humans; Mutation; Plaque, Amyloid

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. - Hyman, Bradley T; Phelps, Creighton H; Beach, Thomas G; Bigio, Eileen H; Cairns, Nigel J; Carrillo, Maria C; Dickson, Dennis W; Duyckaerts, Charles; Frosch, Matthew P; Masliah, Eliezer; Mirra, Suzanne S; Nelson, Peter T; et al. (Alzheimers Dement, 2012)
A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.
Keywords: Alzheimer Disease; Brain; Consensus Development Conferences, NIH as Topic; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; Societies, Medical; United States

Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. - Calderón-Garcidueñas, Lilian; Kavanaugh, Michael; Block, Michelle; D'Angiulli, Amedeo; Delgado-Chávez, Ricardo; Torres-Jardón, Ricardo; González-Maciel, Angelica; Reynoso-Robles, Rafael; Osnaya, Norma; Villarreal-Calderon, Rodolfo; Guo, Ruixin; Hua, Zhaowei; et al. (J Alzheimers Dis, 2012)
Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.
Keywords: Adolescent; Adult; Age Factors; Air Pollution; Child; Child, Preschool; Cohort Studies; Down-Regulation; Encephalitis; Female; Frontal Lobe; Gene Regulatory Networks; Humans; Infant; Male; Mexico; Phosphorylation; Plaque, Amyloid; Prions; tau Proteins; Young Adult

An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. - Jack, Clifford R; Knopman, David S; Weigand, Stephen D; Wiste, Heather J; Vemuri, Prashanthi; Lowe, Val; Kantarci, Kejal; Gunter, Jeffrey L; Senjem, Matthew L; Ivnik, Robert J; Roberts, Rosebud O; Rocca, Walter A; et al. (Ann Neurol, 2012)
OBJECTIVE: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines. METHODS: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria. RESULTS: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP. INTERPRETATION: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biomarkers; Brain; Cognition Disorders; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Longitudinal Studies; Male; Mental Status Schedule; National Institute on Aging (U.S.); Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; United States

A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. - Iliff, Jeffrey J; Wang, Minghuan; Liao, Yonghong; Plogg, Benjamin A; Peng, Weiguo; Gundersen, Georg A; Benveniste, Helene; Vates, G Edward; Deane, Rashid; Goldman, Steven A; Nagelhus, Erlend A; Nedergaard, Maiken (Sci Transl Med, 2012)
Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
Keywords: Amyloid beta-Peptides; Animals; Aquaporin 4; Astrocytes; Biological Transport; Brain; Cerebral Ventricles; Cerebrospinal Fluid; Extracellular Fluid; Imaging, Three-Dimensional; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence, Multiphoton; Water

Predicting regional neurodegeneration from the healthy brain functional connectome. - Zhou, Juan; Gennatas, Efstathios D; Kramer, Joel H; Miller, Bruce L; Seeley, William W (Neuron, 2012)
Neurodegenerative diseases target large-scale neural networks. Four competing mechanistic hypotheses have been proposed to explain network-based disease patterning: nodal stress, transneuronal spread, trophic failure, and shared vulnerability. Here, we used task-free fMRI to derive the healthy intrinsic connectivity patterns seeded by brain regions vulnerable to any of five distinct neurodegenerative diseases. These data enabled us to investigate how intrinsic connectivity in health predicts region-by-region vulnerability to disease. For each illness, specific regions emerged as critical network "epicenters" whose normal connectivity profiles most resembled the disease-associated atrophy pattern. Graph theoretical analyses in healthy subjects revealed that regions with higher total connectional flow and, more consistently, shorter functional paths to the epicenters, showed greater disease-related vulnerability. These findings best fit a transneuronal spread model of network-based vulnerability. Molecular pathological approaches may help clarify what makes each epicenter vulnerable to its targeting disease and how toxic protein species travel between networked brain structures.
Keywords: Aged; Atrophy; Brain; Brain Mapping; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Neural Pathways; Neurodegenerative Diseases; Oxygen; Reference Values

Propagation of tau pathology in a model of early Alzheimer's disease. - de Calignon, Alix; Polydoro, Manuela; Suárez-Calvet, Marc; William, Christopher; Adamowicz, David H; Kopeikina, Kathy J; Pitstick, Rose; Sahara, Naruhiko; Ashe, Karen H; Carlson, George A; Spires-Jones, Tara L; Hyman, Bradley T (Neuron, 2012)
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.
Keywords: Age Factors; Alzheimer Disease; Animals; Disease Models, Animal; Disease Progression; Entorhinal Cortex; Epitopes; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Gliosis; Hippocampus; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; RNA, Messenger; Serine; tau Proteins; Tauopathies

Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. - Bakker, Arnold; Krauss, Gregory L; Albert, Marilyn S; Speck, Caroline L; Jones, Lauren R; Stark, Craig E; Yassa, Michael A; Bassett, Susan S; Shelton, Amy L; Gallagher, Michela (Neuron, 2012)
Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that overactivity in selective hippocampal circuits contributes to cognitive impairment. Here, we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.
Keywords: Aged; Aged, 80 and over; Amnesia; Brain Mapping; Case-Control Studies; Choice Behavior; Double-Blind Method; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Mild Cognitive Impairment; Neuropsychological Tests; Nootropic Agents; Oxygen; Photic Stimulation; Piracetam; Statistics as Topic

18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. - Fodero-Tavoletti, Michelle T; Okamura, Nobuyuki; Furumoto, Shozo; Mulligan, Rachel S; Connor, Andrea R; McLean, Catriona A; Cao, Diana; Rigopoulos, Angela; Cartwright, Glenn A; O'Keefe, Graeme; Gong, Sylvia; Adlard, Paul A; et al. (Brain, 2011)
While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.
Keywords: Alzheimer Disease; Analysis of Variance; Aniline Compounds; Animals; Autoradiography; Binding Sites; Brain; Female; Fluorodeoxyglucose F18; Humans; Immunohistochemistry; Male; Mice; Quinolines; Radiopharmaceuticals; tau Proteins

Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. - Golde, Todd E; Schneider, Lon S; Koo, Edward H (Neuron, 2011)
Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid β-peptide (Aβ) production, aggregation, or accumulation. Translational models suggest that anti-Aβ therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aβ therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aβ aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Clinical Trials as Topic; Disease Progression; Health Services Needs and Demand; Humans; Translational Medical Research

Astrocyte-neuron lactate transport is required for long-term memory formation. - Suzuki, Akinobu; Stern, Sarah A; Bozdagi, Ozlem; Huntley, George W; Walker, Ruth H; Magistretti, Pierre J; Alberini, Cristina M (Cell, 2011)
We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.
Keywords: Animals; Arabinose; Astrocytes; Glycogen; Hippocampus; Imino Furanoses; Lactic Acid; Memory, Long-Term; Monocarboxylic Acid Transporters; Muscle Proteins; Neurons; Rats; Sugar Alcohols; Symporters

Caspase signalling controls microglia activation and neurotoxicity. - Burguillos, Miguel A; Deierborg, Tomas; Kavanagh, Edel; Persson, Annette; Hajji, Nabil; Garcia-Quintanilla, Albert; Cano, Josefina; Brundin, Patrik; Englund, Elisabet; Venero, Jose L; Joseph, Bertrand (Nature, 2011)
Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
Keywords: Alzheimer Disease; Animals; Caspase 3; Caspase 7; Caspase 8; Caspase Inhibitors; Caspases; Cell Death; Cells, Cultured; Dopamine; Enzyme Activation; Frontal Lobe; Gene Knockdown Techniques; Humans; Lipopolysaccharides; Mice; Microglia; Neostriatum; Neurotoxicity Syndromes; Parkinson Disease; Protein Kinase C-delta; Rats; Signal Transduction; Substantia Nigra; Toll-Like Receptor 4

The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - McKhann, Guy M; Knopman, David S; Chertkow, Howard; Hyman, Bradley T; Jack, Clifford R; Kawas, Claudia H; Klunk, William E; Koroshetz, Walter J; Manly, Jennifer J; Mayeux, Richard; Mohs, Richard C; Morris, John C; et al. (Alzheimers Dement, 2011)
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
Keywords: Alzheimer Disease; Biomarkers; Diagnosis, Differential; Diagnostic Imaging; Disease Progression; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; Societies, Medical; United States

The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - Albert, Marilyn S; DeKosky, Steven T; Dickson, Dennis; Dubois, Bruno; Feldman, Howard H; Fox, Nick C; Gamst, Anthony; Holtzman, David M; Jagust, William J; Petersen, Ronald C; Snyder, Peter J; Carrillo, Maria C; et al. (Alzheimers Dement, 2011)
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.
Keywords: Alzheimer Disease; Biomarkers; Cognition Disorders; Diagnosis, Differential; Diagnostic Imaging; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; Societies, Medical; United States

Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. - Qiang, Liang; Fujita, Ryousuke; Yamashita, Toru; Angulo, Sergio; Rhinn, Herve; Rhee, David; Doege, Claudia; Chau, Lily; Aubry, Laetitia; Vanti, William B; Moreno, Herman; Abeliovich, Asa (Cell, 2011)
Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Cell Transdifferentiation; Cells, Cultured; Fibroblasts; Humans; Neurons; Presenilin-1; Presenilin-2; Regenerative Medicine; Skin

Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. - Kapogiannis, Dimitrios; Mattson, Mark P (Lancet Neurol, 2011)
Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans.
Keywords: Alzheimer Disease; Animals; Brain; Cognition Disorders; Energy Metabolism; Humans; Nerve Net

Evidence for ordering of Alzheimer disease biomarkers. - Jack, Clifford R; Vemuri, Prashanthi; Wiste, Heather J; Weigand, Stephen D; Aisen, Paul S; Trojanowski, John Q; Shaw, Leslie M; Bernstein, Matthew A; Petersen, Ronald C; Weiner, Michael W; Knopman, David S (Arch Neurol, 2011)
OBJECTIVE: To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner. DESIGN: Validation sample. SETTING: Multisite, referral centers. PARTICIPANTS: A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples. MAIN OUTCOME MEASURES: Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume). RESULTS: Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months. CONCLUSIONS: A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Hippocampus; Humans; Longitudinal Studies; Male; Mild Cognitive Impairment; tau Proteins

Exercise training increases size of hippocampus and improves memory. - Erickson, Kirk I; Voss, Michelle W; Prakash, Ruchika Shaurya; Basak, Chandramallika; Szabo, Amanda; Chaddock, Laura; Kim, Jennifer S; Heo, Susie; Alves, Heloisa; White, Siobhan M; Wojcicki, Thomas R; Mailey, Emily; et al. (Proc Natl Acad Sci U S A, 2011)
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Keywords: Aged; Aging; Brain-Derived Neurotrophic Factor; Enzyme-Linked Immunosorbent Assay; Exercise; Hippocampus; Humans; Magnetic Resonance Imaging; Memory; Middle Aged; Organ Size; Space Perception

Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. - Castellano, Joseph M; Kim, Jungsu; Stewart, Floy R; Jiang, Hong; DeMattos, Ronald B; Patterson, Bruce W; Fagan, Anne M; Morris, John C; Mawuenyega, Kwasi G; Cruchaga, Carlos; Goate, Alison M; Bales, Kelly R; et al. (Sci Transl Med, 2011)
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.
Keywords: Adult; Aged; Alleles; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoprotein E4; Biomarkers; Brain; Female; Genotype; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microdialysis; Middle Aged; Protein Isoforms

Neuronal activity regulates the regional vulnerability to amyloid-β deposition. - Bero, Adam W; Yan, Ping; Roh, Jee Hoon; Cirrito, John R; Stewart, Floy R; Raichle, Marcus E; Lee, Jin-Moo; Holtzman, David M (Nat Neurosci, 2011)
Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Disease Models, Animal; Extracellular Fluid; Female; Lactic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microdialysis; Neurons; Plaque, Amyloid; Sensory Deprivation; Somatosensory Cortex

Neuronal basis of age-related working memory decline. - Wang, Min; Gamo, Nao J; Yang, Yang; Jin, Lu E; Wang, Xiao-Jing; Laubach, Mark; Mazer, James A; Lee, Daeyeol; Arnsten, Amy F T (Nature, 2011)
Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.
Keywords: Action Potentials; Adrenergic alpha-2 Receptor Agonists; Aging; Animals; Biomedical Enhancement; Cues; Cyclic AMP; Cyclic Nucleotide-Gated Cation Channels; Guanfacine; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; KCNQ Potassium Channels; Macaca mulatta; Male; Memory, Short-Term; Models, Neurological; Neural Pathways; Potassium Channel Blockers; Potassium Channels; Prefrontal Cortex; Receptors, Adrenergic, alpha-2; Signal Transduction; Time Factors

Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. - Jucker, Mathias; Walker, Lary C (Ann Neurol, 2011)
The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; DNA-Binding Proteins; Humans; Neurodegenerative Diseases; Prions; Proteins; tau Proteins

Report of the task force on designing clinical trials in early (predementia) AD. - Aisen, P S; Andrieu, S; Sampaio, C; Carrillo, M; Khachaturian, Z S; Dubois, B; Feldman, H H; Petersen, R C; Siemers, E; Doody, R S; Hendrix, S B; Grundman, M; et al. (Neurology, 2011)
BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.
Keywords: Advisory Committees; Alzheimer Disease; Amyloidogenic Proteins; Biomarkers; Clinical Trials as Topic; Cognition; Consensus; Disease Progression; Drug Industry; Early Diagnosis; Europe; Humans; Indans; International Cooperation; Nootropic Agents; Outcome Assessment (Health Care); Patient Selection; Piperidines; Positron-Emission Tomography; Research Design; Treatment Outcome; United States; United States Food and Drug Administration; Vitamin E

Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. - Jin, Ming; Shepardson, Nina; Yang, Ting; Chen, Gang; Walsh, Dominic; Selkoe, Dennis J (Proc Natl Acad Sci U S A, 2011)
Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Chromatography, Gel; Dimerization; Genetic Vectors; Hippocampus; Humans; Immunohistochemistry; Immunoprecipitation; In Situ Nick-End Labeling; Lentivirus; Microscopy, Confocal; Microtubules; Neurites; Phosphorylation; Rats; Rats, Sprague-Dawley; tau Proteins

Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. - Braak, Heiko; Thal, Dietmar R; Ghebremedhin, Estifanos; Del Tredici, Kelly (J Neuropathol Exp Neurol, 2011)
Two thousand three hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined using immunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8) and Campbell-Switzer staining were used for the detection ofβ-amyloid. A total of 342 cases was negative in the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases had subcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcortical Stages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinal region (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236 cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallel with NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Of the total cases, 1,031 (44.2%) had β-amyloid plaques. The first plaques occurred in the neocortex after the onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases, culminating in their tenth decade (75%). β-amyloid plaques and NFTs were significantly correlated (p < 0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Brain; Child; Child, Preschool; Cohort Studies; Disease Progression; Female; Humans; Infant; Male; Middle Aged; Neurofibrillary Tangles; Neurons; Silver Staining; Statistics, Nonparametric; tau Proteins; Young Adult

Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - Sperling, Reisa A; Aisen, Paul S; Beckett, Laurel A; Bennett, David A; Craft, Suzanne; Fagan, Anne M; Iwatsubo, Takeshi; Jack, Clifford R; Kaye, Jeffrey; Montine, Thomas J; Park, Denise C; Reiman, Eric M; et al. (Alzheimers Dement, 2011)
The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
Keywords: Alzheimer Disease; Biomarkers; Cognition Disorders; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; United States

Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. - Li, J; Wang, Y J; Zhang, M; Xu, Z Q; Gao, C Y; Fang, C Q; Yan, J C; Zhou, H D (Neurology, 2011)
OBJECTIVE: Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. METHODS: A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion. RESULTS: At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion. CONCLUSION: VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.
Keywords: Aged; Alzheimer Disease; Cerebrovascular Disorders; Cognition Disorders; Disease Progression; Female; Humans; Incidence; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptides; Regression Analysis; Residence Characteristics; Retrospective Studies; Risk Factors; Statistics, Nonparametric

Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. - Petersen, R C; Aisen, P S; Beckett, L A; Donohue, M C; Gamst, A C; Harvey, D J; Jack, C R; Jagust, W J; Shaw, L M; Toga, A W; Trojanowski, J Q; Weiner, M W (Neurology, 2010)
BACKGROUND: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally. OBJECTIVE: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures. METHODS: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials. RESULTS: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures. CONCLUSION: The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cross-Sectional Studies; Diagnostic Imaging; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Middle Aged

APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. - Morris, John C; Roe, Catherine M; Xiong, Chengjie; Fagan, Anne M; Goate, Alison M; Holtzman, David M; Mintun, Mark A (Ann Neurol, 2010)
OBJECTIVE: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging. METHODS: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE. RESULTS: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181). INTERPRETATION: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Brain; Female; Follow-Up Studies; Genotype; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Phosphorylation; Plaque, Amyloid; tau Proteins; Thiazoles

Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. - Miller, Jeremy A; Horvath, Steve; Geschwind, Daniel H (Proc Natl Acad Sci U S A, 2010)
Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human, we took a systems-biology approach by using weighted gene coexpression network analysis on more than 1,000 microarrays from brain. We find that global network properties of the brain transcriptome are highly preserved between species. Furthermore, all modules of highly coexpressed genes identified in mouse were identified in human, with those related to conserved cellular functions showing the strongest between-species preservation. Modules corresponding to glial and neuronal cells were sufficiently preserved between mouse and human to permit identification of cross species cell-class marker genes. We also identify several robust human-specific modules, including one strongly correlated with measures of Alzheimer disease progression across multiple data sets, whose hubs are poorly-characterized genes likely involved in Alzheimer disease. We present multiple lines of evidence suggesting links between neurodegenerative disease and glial cell types in human, including human-specific correlation of presenilin-1 with oligodendrocyte markers, and significant enrichment for known neurodegenerative disease genes in microglial modules. Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders.
Keywords: Alzheimer Disease; Animals; Brain; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; Mice; Presenilin-1; Systems Biology

Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. - He, Gen; Luo, Wenjie; Li, Peng; Remmers, Christine; Netzer, William J; Hendrick, Joseph; Bettayeb, Karima; Flajolet, Marc; Gorelick, Fred; Wennogle, Lawrence P; Greengard, Paul (Nature, 2010)
Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer's disease. Formation of amyloid-beta is catalysed by gamma-secretase, a protease with numerous substrates. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective gamma-secretase inhibitors that can reduce amyloid-beta formation without impairing cleavage of other gamma-secretase substrates, especially Notch, which is essential for normal biological functions. Here we report the discovery of a novel gamma-secretase activating protein (GSAP) that drastically and selectively increases amyloid-beta production through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-beta production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-beta concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-beta and plaque development. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-beta formation without affecting Notch cleavage, achieves its amyloid-beta-lowering effect by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Benzamides; Cell Line; Disease Models, Animal; Gene Knockdown Techniques; Humans; Imatinib Mesylate; Mice; Peptide Fragments; Piperazines; Proteins; Pyrimidines; Receptor, Notch1; RNA Interference

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. - Jones, Lesley; Holmans, Peter A; Hamshere, Marian L; Harold, Denise; Moskvina, Valentina; Ivanov, Dobril; Pocklington, Andrew; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Pahwa, Jaspreet Singh; et al. (PLoS One, 2010)
BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
Keywords: Alzheimer Disease; Apolipoproteins E; Cholesterol; Chromosome Mapping; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Immune System; Polymorphism, Single Nucleotide

Memory impairment in transgenic Alzheimer mice requires cellular prion protein. - Gimbel, David A; Nygaard, Haakon B; Coffey, Erin E; Gunther, Erik C; Laurén, Juha; Gimbel, Zachary A; Strittmatter, Stephen M (J Neurosci, 2010)
Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Avoidance Learning; Brain; Disease Models, Animal; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Degeneration; Presenilin-1; PrPC Proteins; Random Allocation; Serotonin; Survival Analysis

National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. - Daviglus, Martha L; Bell, Carl C; Berrettini, Wade; Bowen, Phyllis E; Connolly, E Sander; Cox, Nancy Jean; Dunbar-Jacob, Jacqueline M; Granieri, Evelyn C; Hunt, Gail; McGarry, Kathleen; Patel, Dinesh; Potosky, Arnold L; et al. (Ann Intern Med, 2010)
The National Institute on Aging and the Office of Medical Applications of Research of the National Institutes of Health convened a State-of-the-Science Conference on 26-28 April 2010 to assess the available scientific evidence on prevention of cognitive decline and Alzheimer disease. This article provides the panel's assessment of the available evidence.
Keywords: Aged; Alzheimer Disease; Cognition Disorders; Evidence-Based Medicine; Humans; Risk Factors; Risk Reduction Behavior

Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy. - McGeer, Edith G; McGeer, Patrick L (J Alzheimers Dis, 2010)
Neuroinflammation is a prominent feature of Alzheimer disease (AD) and other chronic neurodegenerative disorders. It exacerbates the fundamental pathology by generating a plethora of inflammatory mediators and neurotoxic compounds. Inflammatory cytokines, complement components, and toxic free radicals are among the many species that are generated. Microglia attack the pathological entities and may inadvertently injure host neurons. Recent evidence indicates that microglia can be stimulated to assume an antiinflammatory state rather than a proinflammatory state which may have therapeutic potential. Proinflammatory cytokines include IL-1, IL-6 and TNF, while antiinflammatory cytokines include IL-4 and IL-10. Complement activation is a separate process which causes extensive neuronal damage in AD through assembly of the membrane attack complex. Aggregated amyloid-beta is a potent activator of human complement but not of mouse complement. This is an important difference between AD and transgenic mouse models of AD. Many so far unexplored molecules may contribute to neuroinflammation or act to inhibit it. Stable isotope labeling by amino acids in cell culture (SILAC) analysis identified 174 proteins that were upregulated by two-fold or more, and 189 that were downregulated by 2-fold or more following inflammatory stimulation of microglial-like THP-1 cells. Neurotoxicity may result from any combination of these and further exploration is clearly warranted. In addition, many small molecules may play a significant role. One example is hydrogen sulfide which appears to be an endogenous antiinflammatory agent.
Keywords: Alzheimer Disease; Animals; Cognition Disorders; Humans; Inflammation; Neurology

Tau in Alzheimer disease and related tauopathies. - Iqbal, K; Liu, F; Gong, C-X; Grundke-Iqbal, I (Curr Alzheimer Res, 2010)
Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.
Keywords: Alzheimer Disease; Animals; Humans; Phosphorylation; tau Proteins; Tauopathies