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Introduction: Older individuals with a higher cardiovascular disease (CVD) burden have a higher risk for accelerated cognitive decline and dementia. Physical activity (PA) is an inexpensive and accessible preventive measure to CVD, cognitive impairment, and dementia. The current study examined (1) whether PA moderates the relationship between CVD burden and cognition and (2) whether the moderating effect of PA differs by race/ethnicity groups and by APOE-ɛ4 status., Methods: Our cross-sectional study included participants from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, community-based, longitudinal study on aging and dementia among individuals aged 65 years and older who reside in northern Manhattan. All participants underwent an interview and a neuropsychological assessment for global cognition, memory, language, visuospatial, and speed functioning., Results: In 2,122 older individuals without dementia, having a higher CVD burden was associated with worse cognitive scores for global, language, speed, and visuospatial cognitive functions. PA mitigated the relationship between CVD burden and visuospatial function. Furthermore, PA mitigated the association of CVD burden with global cognition, language, and visuospatial functions in APOE-ɛ4 carriers but not in non-carriers., Discussion/conclusion: Our study suggests that PA may mitigate the negative association between CVD and cognition, especially in APOE-ɛ4 carriers. The moderating effect of PA did not differ by race/ethnicity., Introduction: Older individuals with a higher cardiovascular disease (CVD) burden have a higher risk for accelerated cognitive decline and dementia. Physical activity (PA) is an inexpensive and accessible preventive measure to CVD, cognitive impairment, and dementia. The current study examined (1) whether PA moderates the relationship between CVD burden and cognition and (2) whether the moderating effect of PA differs by race/ethnicity groups and by APOE-ɛ4 status., Methods: Our cross-sectional study included participants from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, community-based, longitudinal study on aging and dementia among individuals aged 65 years and older who reside in northern Manhattan. All participants underwent an interview and a neuropsychological assessment for global cognition, memory, language, visuospatial, and speed functioning., Results: In 2,122 older individuals without dementia, having a higher CVD burden was associated with worse cognitive scores for global, language, speed, and visuospatial cognitive functions. PA mitigated the relationship between CVD burden and visuospatial function. Furthermore, PA mitigated the association of CVD burden with global cognition, language, and visuospatial functions in APOE-ɛ4 carriers but not in non-carriers., Discussion/conclusion: Our study suggests that PA may mitigate the negative association between CVD and cognition, especially in APOE-ɛ4 carriers. The moderating effect of PA did not differ by race/ethnicity., (© 2024 S. Karger AG, Basel.)

Introduction: We investigated whether early life exposure to state-level structural sexism influenced late-life memory trajectories among United Staes (U.S.) -born women and men and determined whether associations differed between racialized groups., Methods: Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; N = 2314) and Health and Retirement Study (HRS; N = 18,631). State-level structural sexism was measured via U.S. census and administrative data and linked to participants in each study by birth year and state., Results: Exposure to greater structural sexism was associated with lower baseline memory performance among WHICAP women and HRS men and faster memory decline among women in both studies. Women born in the state with the highest structural sexism showed memory decline like that of those who were 9 years older. Structural sexism-baseline memory associations were stronger among Black women than White women., Discussion: Early life exposure to structural sexism negatively impacts late-life memory trajectories among women., Highlights: A longitudinal measure captured state-level structural sexism from 1900 to 1960. Exposure to structural sexism was associated with worse late-life memory outcomes. Associations were strongest among women for memory decline. The negative impact on memory performance was stronger among Black women. Lowering structural sexism may, in turn, reduce memory decline among women., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's Disease and Related Dementias (AD/ADRD) by sequencing whole genomes of affected participants and age-matched cognitive controls from diverse populations. The Genome Center for Alzheimer's Disease (GCAD) processed whole-genome sequencing data from 36,361 ADSP participants, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4). This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 2.2 million structural variants. Annotations and quality control data are available for all variants and samples. Additionally, detailed phenotypes from 15,927 participants across 10 domains are also provided. A linkage disequilibrium panel was created using unrelated AD cases and controls. Researchers can access and analyze the genetic data via NIAGADS Data Sharing Service, the VariXam tool, or NIAGADS GenomicsDB.

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk., (© 2024. The Author(s).)

Objective: Routine health care visits offer the opportunity to screen older adults for symptoms of Alzheimer's disease (AD). Many women see their gynecologist as their primary health care provider. Given this unique relationship, the Women's Preventive Services Initiative and the American College of Obstetrics and Gynecology advocate for integrated care of women at all ages. It is well-established that women are at increased risk for AD, and memory screening of older women should be paramount in this effort. Research is needed to determine the feasibility and value of memory screening among older women at the well-woman visit. Materials and Methods: Women aged 60 and above completed a 5-item subjective memory screener at their well-woman visit at the Columbia University Integrated Women's Health Program. Women who endorsed any item were considered to have a positive screen and were given the option to pursue clinical evaluation. Rates of positive screens, item endorsement, and referral preferences were examined. Results: Of the 530 women approached, 521 agreed to complete the screener. Of those, 17.5% ( n = 91) were classified as positive. The most frequently endorsed item was difficulty with memory or thinking compared with others the same age. Among women with positive screens, 57.5% were interested in pursuing clinical referrals to a memory specialist. Conclusion: Results support the feasibility and potential value of including subjective memory screening as part of a comprehensive well-woman program. Early identification of memory loss will enable investigation into the cause of memory symptoms and longitudinal monitoring of cognitive change.

Background: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear., Methods: We conducted the largest sex-aware genetic study on late-life memory to date (N males  = 11,942; N females  = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants., Results: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits., Discussion: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory., Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline., Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts., Results: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits., Discussion: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline., Highlights: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community., (© 2024. The Author(s).)

Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-β, and microglial ADPRS was associated with amyloid-β and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage., (© 2023. The Author(s).)

Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes., Methods: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software., Results: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10 -9 ). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10 -8 ) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10 -8 ). GRN (rs5848, P = 4.21 × 10 -8 ) and PURG (rs117523305, P = 1.73 × 10 -8 ) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10 -8 ) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10 -9 ) and PTPRD (rs145989094, P = 8.34 × 10 -9 ) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10 -8 ) and PTPRD (rs145989094, P = 3.85 × 10 -8 ) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD., Conclusion: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias., (© 2023. The Author(s).)

Background: This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions., Methods: We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes., Results: Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10 -5 ) and 18q21.33 (p = 1.2 × 10 -5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2., Discussion: Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus., Highlights: We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations., (© 2022 the Alzheimer's Association.)

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10 -311 , MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10 -09 , MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10 -10 , MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10 -09 , MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10 -08 , MAF = 0.006, sex-interaction P = 9.8 × 10 -07 ) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10 -08 , MAF = 0.004, sex-interaction P = 1.3 × 10 -03 ). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies., (© 2023. The Author(s).)

Background and Objectives: This prospective study seeks to examine the utility of subjective cognitive decline (SCD) as a marker of future progression to dementia in a community-based cohort of non-Latinx White, non-Latinx Black, and Latinx individuals. Debate surrounds the utility of SCD, the subjective perception of decline in one's cognition before such impairment is evident in traditional neuropsychological assessments, as an early indicator of impending Alzheimer disease. Unfortunately, most studies examining SCD have been conducted in non-Latinx White samples and commonly exclude groups of individuals shown to be most vulnerable to dementia., Methods: Participants were enrolled into this cohort study from the Washington Heights-Inwood Columbia Aging Project if they were cognitively unimpaired, had baseline measurement of SCD, and self-identified as non-Latinx White, non-Latinx Black, or Latinx. SCD was measured as a continuous sum of 10 items assessing cognitive complaints. Competing risk models tested the main effects of baseline SCD on progression to dementia. Models were adjusted for age, sex/gender, years of education, medical comorbidity burden, enrollment cohort, and baseline memory test performance with death jointly modelled as a function of race/ethnicity., Results: A total of 4,043 (1,063 non-Latinx White, 1,267 non-Latinx Black, and 1,713 Latinx) participants were selected for this study with a mean age of 75 years, 67% women, and with a mean follow-up of 5 years. Higher baseline SCD was associated with increased rates of incident dementia over time in the full sample (hazard ratio [HR] 1.085, CI 1.047-1.125, p < 0.001) and within Latinx (HR 1.084, CI 1.039-1.130, p < 0.001) and non-Latinx Black individuals (HR 1.099, CI 1.012-1.194, p = 0.024)., Discussion: Overall results of this study support SCD as a prodromal marker of dementia in a multiracial community sample, and in Latinx and non-Latinx Black individuals in particular. Because models examining the risk of dementia were adjusted for baseline memory test performance, the results support the idea that SCD, a subjective reflection of one's own current cognitive functioning, contributes information above and beyond standard memory testing. Current findings highlight the importance of carefully evaluating any memory concerns raised by older adults during routine visits and underscore the potential utility of screening older adults for SCD., (© 2022 American Academy of Neurology.)

Introduction: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI., Methods: A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed-effects models examined association between age and single nucleotide variants (SNVs)., Results: Three SNVs were significantly associated (P < 5 × 10 -8 ) with AAO on chromosomes 6 (rs14538074; hazard ratio [HR] = 3.35), 9 (rs534551495; HR = 2.82), and 17 (rs146729640; HR = 6.38). The chromosome 17 association was replicated in the independent National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease dataset., Discussion: The replicated genome-wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease., (© 2022 the Alzheimer's Association.)

Background: Current evidence on the association between Mediterranean diet (MeDi) intake and activities of daily living (ADL) is limited and inconsistent in older adults., Methods: This study included 1 696 participants aged ≥65 years in the Washington Heights-Inwood Community Aging Project study. The MeDi score was calculated based on data collected from the Willett's semiquantitative food frequency questionnaire. The multivariable-adjusted Cox regression model was applied to examine the association of MeDi score with risks of disability in basic (BADL) and instrumental ADL (IADL), as well as the overall ADL (B-IADL)., Results: Eight hundred and thirty-two participants with incident ADL disability were identified over a median follow-up of 5.39 years. The continuous MeDi score was significantly associated with decreased risk of disability in B-IADL (hazard ratio = 0.95, 95% confidence interval = 0.91-0.99, p = .018) in a model adjusted for age, sex, race/ethnicity, educational level, and dietary calories intake but was no longer significant after additionally adjusted for multiple comorbidities and physical activities (0.97 [0.93, 1.01], p = .121). The continuous MeDi score was significantly associated with decreased risk of disability in B-IADL (0.92 [0.85, 1.00], p = .043) and BADL (0.90 [0.82, 0.99], p = .030) in non-Hispanic Whites, but not in non-Hispanic Blacks and Hispanics (p > .05 for all)., Conclusions: Higher MeDi score was associated with decreased risk of ADL disability, particularly in non-Hispanic Whites., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS ( n  = 3382) and Stage 2 mega-analysis ( n  = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p  =  1.8 × 10 - 7 ; rs2603462, p  =  4 × 10 - 7 ) were significant in the ADNI cohort (rs7902929, p  =  0.012 ; rs2603462, p = 0.012 ). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3 . We thus identified putative loci associated with B-ASC risk, but additional replication is needed.

Introduction: There is limited and inconsistent reporting on the association between Life's Simple 7 (LS7) and dementia in the elderly population., Methods: Based on the Washington Heights-Inwood Columbia Aging Project (WHICAP), LS7 scores were estimated to assess cardiovascular health status. Associations between LS7 scores and incident dementia were investigated by Cox proportional hazards models., Results: Among 1987 subjects, 291 incident cases of dementia were identified over a median follow-up of 5.84 years. Compared with subjects in the poor cardiovascular health group (scores 0 to 5), those in intermediate (6 to 9) and optimal (10 to 14) groups had lower dementia risk, with the hazard ratio (HR; 95% confidence interval) being 0.74 (0.54 to 1.00) and 0.59 (0.38 to 0.91), respectively. These results were significant in apolipoprotein E genotype ε4 (APOE ε4) allele non-carriers but not in carriers., Discussion: Higher LS7 scores are protective for dementia, especially among the APOE ε4 noncarriers., (© 2021 the Alzheimer's Association.)

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD., (Copyright © 2021. Published by Elsevier Inc.)

Objective: This study aimed to investigate the association between dietary prebiotic intake and risk for Alzheimer's disease (AD)., Methods: This longitudinal study includes 1,837 elderly (≥65 years) participants of a multi-ethnic community-based cohort study who were dementia-free at baseline and had provided dietary information from food frequency questionnaires. Total daily intake of fructan, one of the best-known prebiotics, was calculated based on consumption frequency and fructan content per serving of 8 food items. The associations of daily fructan intake with AD risk were examined using a Cox proportional hazards model, adjusted for cohort recruitment wave, age, gender, race/ethnicity, education, daily caloric intake, and APOE genotype. Effect modification by race/ethnicity, APOE genotype, and gender was tested by including an interaction term into the Cox models, as well as by stratified analyses., Results: Among 1,837 participants (1,263 women [69%]; mean [SD] age = 76 [6.3] years), there were 391 incident AD cases during a mean follow-up of 7.5 years (13736 person-years). Each additional gram of fructan intake was associated with 24% lower risk for AD ((95% CI)=0.60-0.97; P =0.03). Additional adjusting for smoking, alcohol consumption, and comorbidity index did not change results materially. The associations were not modified by race/ethnicity, gender, and APOE genotype, although stratified analyses showed that fructan intake was significantly associated with reduced AD risk in Hispanics but not in non-Hispanic Blacks or Whites., Conclusion: Higher dietary fructan intake is associated with a reduced risk of clinical Alzheimer's disease among older adults., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Importance: Results from longitudinal studies suggest that regular leisure time physical activity (LTPA) is associated with reduced risk of dementia or Alzheimer disease. Data on the association between LTPA and brain magnetic resonance imaging (MRI) measures remain scarce and inconsistent., Objective: To examine the association of LTPA and MRI-assessed brain aging measures in a multiethnic elderly population., Design, Setting, and Participants: This cross-sectional study included 1443 older (≥65 years) adults without dementia who were participants of the Washington/Hamilton Heights-Inwood Columbia Aging Project study. LTPA, from self-reported questionnaire, was calculated as metabolic equivalent of energy expenditure. Both moderate to vigorous LTPA, assessed as meeting Physical Activity Guidelines for Americans (≥150 minutes/week) or not, and light-intensity LTPA were also examined., Exposures: LTPA., Main Outcomes and Measures: Primary outcomes included total brain volume (TBV), cortical thickness, and white matter hyperintensity volume, all derived from MRI scans with established methods and adjusted for intracranial volume when necessary. We examined the association of LTPA with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors., Results: The 1443 participants of the study had a mean (SD) age of 77.2 (6.4) years; 921 (63.8%) were women; 27.0%, 34.4%, and 36.3% were non-Hispanic White, non-Hispanic African American, and Hispanic individuals, respectively; and 27.3% carried the apolipoprotein E (APOE) ɛ4 allele. Compared with the LTPA of nonactive older adults, those with the most LTPA had larger (in cm3) TBV (β [SE], 13.17 [4.42] cm3; P = .003; P for trend = .006) and greater cortical thickness (β [SE], 0.016 [0.008] mm; P = .05; P for trend = .03). The effect size comparing the highest LTPA level with the nonactive group was equivalent to approximately 3 to 4 years of aging (β for 1 year older, -3.06 and -0.005 for TBV and cortical thickness, respectively). A dose-response association was found and even the lowest LTPA level had benefits (eg, TBV: β [SE], 9.03 [4.26] cm3; P = .03) compared with the nonactive group. Meeting Physical Activity Guidelines for Americans (TBV: β [SE], 18.82 [5.14] cm3; P < .001) and light-intensity LTPA (TBV: β [SE], 9.26 [4.29] cm3; P = .03) were also associated with larger brain measures. The association between LTPA and TBV was moderated by race/ethnicity, sex, and APOE status, but generally existed in all subgroups. The results remained similar after excluding participants with mild cognitive impairment., Conclusions and Relevance: In this study, more physical activity was associated with larger brain volume in older adults. Longitudinal studies are warranted to explore the potential role of physical activity in brain health among older individuals.

Background: It is important to assess the temporal reproducibility of circulating cytokines for their utility in epidemiological studies. However, existing evidence is limited and inconsistent, especially for the elderly population., Methods: Sixty-five elderly (mean age = 77.89 ± 6.14 years) subjects were randomly selected from an existing prospective cohort study. Levels of 41 cytokines in 195 serum samples, collected at three separate visits that were up to 15.26 years apart, were measured by the Luminex technology. The temporal reproducibility of cytokines was estimated by the intraclass correlation coefficient (ICC) calculated using a mixed-effects model. In addition, data analyses were stratified by the median (4.49 years) of time intervals across sample collection. Sensitivity analyses were performed when excluding subjects with undetectable samples., Results: A total of 23 cytokines were detectable in more than 60% of samples. Fair to good (ICC = 0.40 to 0.75) and excellent (ICC > 0.75) reproducibility was found in 10 (Eotaxin, VEGF, FGF-2, G-CSF, MDC, GM-CSF, TGFα, IP-10, MIP-1β, IL-1RA) and 5 (GRO, IFNγ, IL-17, PDGF-AA, IL-4) cytokines, respectively. The results were not changed dramatically in the stratification and sensitivity analyses., Conclusions: Serum levels of the selected 15 cytokines measured with Luminex technology displayed fair to excellent within-person temporal reproducibility among elderly population., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

Our group has previously studied the brains of some unique individuals who are able to tolerate robust amounts of Alzheimer's pathological lesions (amyloid plaques and neurofibrillary tangles) without experiencing dementia while alive. These rare resilient cases do not demonstrate the patterns of neuronal/synaptic loss that are normally found in the brains of typical demented Alzheimer's patients. Moreover, they exhibit decreased astrocyte and microglial activation markers GFAP and CD68, suggesting that a suppressed neuroinflammatory response may be implicated in human brain resilience to Alzheimer's pathology. In the present work, we used a multiplexed immunoassay to profile a panel of 27 cytokines in the brains of controls, typical demented Alzheimer's cases, and two groups of resilient cases, which possessed pathology consistent with either high probability (HP, Braak stage V-VI and CERAD 2-3) or intermediate probability (IP, Braak state III-IV and CERAD 1-3) of Alzheimer's disease in the absence of dementia. We used a multivariate partial least squares regression approach to study differences in cytokine expression between resilient cases and both Alzheimer's and control cases. Our analysis identified distinct profiles of cytokines in the entorhinal cortex (one of the earliest and most severely affected brain regions in Alzheimer's disease) that are up-regulated in both HP and IP resilient cases relative to Alzheimer's and control cases. These cytokines, including IL-1β, IL-6, IL-13, and IL-4 in HP resilient cases and IL-6, IL-10, and IP-10 in IP resilient cases, delineate differential inflammatory activity in brains resilient to Alzheimer's pathology compared to Alzheimer's cases. Of note, these cytokines all have been associated with pathogen clearance and/or the resolution of inflammation. Moreover, our analysis in the superior temporal sulcus (a multimodal association cortex that consistently accumulates Alzheimer's pathology at later stages of the disease along with overt symptoms of dementia) revealed increased expression of neurotrophic factors, such as PDGF-bb and basic FGF in resilient compared to AD cases. The same region also had reduced expression of chemokines associated with microglial recruitment, including MCP-1 in HP resilient cases and MIP-1α in IP resilient cases compared to AD. Altogether, our data suggest that different patterns of cytokine expression exist in the brains of resilient and Alzheimer's cases, link these differences to reduced glial activation, increased neuronal survival and preserved cognition in resilient cases, and reveal specific cytokine targets that may prove relevant to the identification of novel mechanisms of brain resiliency to Alzheimer's pathology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Multipoint linkage analysis is an important approach for localizing disease-associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed populations are particularly susceptible to this problem because of the challenge of accurately accounting for population structure. Therefore, increasing emphasis on use of multiethnic samples in genetic studies requires reevaluation of best practices, given data currently available. Typical strategies have been to compute allele frequencies from the sample, or to use marker allele frequencies determined by admixture proportions averaged over the entire sample. However, admixture proportions vary among pedigrees and throughout the genome in a family-specific manner. Here, we evaluate several approaches to model admixture in linkage analysis, providing different levels of detail about ancestral origin. To perform our evaluations, for specification of marker allele frequencies, we used data on 67 Caribbean Hispanic admixed families from the Alzheimer's Disease Sequencing Project. Our results show that choice of admixture model has an effect on the linkage analysis results. Variant-specific admixture proportions, computed for individual families, provide the most detailed regional admixture estimates, and, as such, are the most appropriate allele frequencies for linkage analysis. This likely decreases the number of false-positive results, and is straightforward to implement., (© 2018 WILEY PERIODICALS, INC.)

Background: Accumulating evidence suggests that dietary factors are associated with Alzheimer's disease, cognition, and brain health in older adults. It is however unclear whether inflammation explains this association., Objective: To examine whether an inflammation-related nutrient pattern (INP) was associated with neuroimaging and cognitive measures of brain health., Method: The current cross-sectional study included 330 non-demented elderly (mean age 79 years at MRI scan) participants in a multi-ethnic, community-based cohort study who had information on nutritional intake (estimated from food frequency questionnaire), circulating C-reactive protein and interleukin- 6 (measured by ELISA), MRI scans, and cognition. Diet and blood samples were collected approximately 5.3 years prior to the MRI and cognitive test visit. We used a reduced rank regression model to derive an INP based on 24 nutrients' relationship with CRP and interleukin-6. We examined the association of the INP with brain and cognitive measures using regression models adjusted for age, sex, race/ethnicity, education, caloric intake, APOE genotype, body mass index, and vascular burden, as well as intracranial volume for the brain MRI measures., Results: The INP was characterized by low intake (effect loading <-0.15) of calcium, vitamins (D, E, A, B1, B2, B3, B5, B6), folate, Ω-3 poly-unsaturated fatty acids, and high intake (>0.15) of cholesterol. As designed, this INP was positively correlated with CRP (Pearson's r=0.25 p=0.005) and interleukin-6 (r=0.30, p<0.0001). Each unit increase in INP was associated with 36.8 cm3 (p=0.023) smaller total brain volume and 0.21 (p=0.038) lower visuospatial z-score. Mediation analysis showed that TGMV (b=0.002, p=0.003) was associated with visuospatial cognitive function, and there was a significant mediation effect by TGMV (indirect effect: -0.049, 95% CI: -0.1121 ~ -0.0131) for the association between INP and visuospatial cognitive score., Conclusions: Among older adults, a diet with high inflammatory potential is associated with less favorable brain and cognitive health., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD)., Methods: Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk., Results: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10 -7 ) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10 -7 ) and sLOAD (OR = 1.40; P = 1.21 × 10 -3 ). The PRS was associated with cerebrospinal fluid ptau 181 -Aβ 42 on eADAD (P = 4.36 × 10 -2 )., Conclusion: Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials., Methods: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point., Results: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point., Discussion: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Importance: Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD., Objective: To search for rare variants contributing to the risk for EOAD., Design, Setting, and Participants: In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016., Main Outcomes and Measures: Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively., Results: Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10-6; Bonferroni-corrected P value [BP] = 1.3 × 10-3) and LOAD (P = 6.22 × 10-6; BP = 4.1 × 10-3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10-4; BP = 5.0 × 10-3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129)., Conclusions and Relevance: The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport-a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2.

Background: Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD., Methods: We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms., Findings: The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55·1%, 95% CI 45·7-64·6), aphasia (57·9%, 48·6-67·3), and behavioural changes (61·7%, 51·5-70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9-7·2], aphasia [23·0%, 20·0-26·0], and behavioural changes [31·7%, 28·4-35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8-15·0), and seizures (2·8%, 0·5-5·9) and moderate for parkinsonism (11·2%, 5·3-17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6-22·2 and 15·0%, 12·5-17·6, respectively), parkinsonism (12·5%, 10·1-15·0), and seizures (20·3%, 17·4-23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04-1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90-0·97, p=0·0007; seizures 0·95, 0·92-0·98, p=0·0018; corticobulbar deficits 0·91, 0·86-0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74-0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease., Interpretation: The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms., Funding: National Institutes of Health and German Center for Neurodegenerative Diseases., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found., Methods: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles., Results: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir&#95;320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases., Discussion: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inbreeding can be associated with a modification of disease risk due to excess homozygosity of recessive alleles affecting a wide range of phenotypes. We estimated the inbreeding coefficient in Caribbean Hispanics and examined its effects on risk of late-onset Alzheimer disease., Methods: The inbreeding coefficient was calculated in 3,392 subjects (1,451 late-onset Alzheimer disease patients and 1,941 age-matched healthy controls) of Caribbean Hispanic ancestry using 177,997 nearly independent single-nucleotide polymorphisms from genome-wide array. The inbreeding coefficient was estimated using the excess homozygosity method with and without adjusting for admixture., Results: The average inbreeding coefficient in Caribbean Hispanics without accounting for admixture was F = 0.018 (±0.048), suggesting a mating equivalent to that of second cousins or second cousins once removed. Adjusting for admixture from three parent populations, the average inbreeding coefficient was found to be 0.0034 (±0.019) or close to third-cousin mating. Inbreeding coefficient was a significant predictor of Alzheimer disease when age, sex, and APOE genotype were used as adjusting covariates (P = 0.03)., Conclusion: The average inbreeding coefficient of this population is significantly higher than that of the general Caucasian populations in North America. The high rate of inbreeding resulting in increased frequency of recessive variants is advantageous for the identification of rare variants associated with late-onset Alzheimer disease.Genet Med 17 8, 639-643.

Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants., Objectives: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium., Design, Setting, and Participants: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes., Main Outcomes and Measures: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria., Results: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242)., Conclusions and Relevance: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD., Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study., Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10(-16), r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex., Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research., (© 2014 American Academy of Neurology.)

Objectives: To determine if plasma β-amyloid (Aβ) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease (AD) and (2) correspond to cognitive change independent of dementia., Design: Longitudinal study including 3 visits during approximately 4¹/₂ years (2000-2006)., Setting: Northern Manhattan community., Participants: Eight hundred eighty individuals from a population-based and ethnically diverse sample who had 2 plasma Aβ measurements and were dementia free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed AD., Main Outcome Measures: General estimating equations tested the association between plasma Aβ (baseline and change in values) and cognitive change (composite score and memory, language, and visuospatial indices)., Results: High baseline plasma Aβ42 (P = .01) and Aβ40 (P = .01) and decreasing/relatively stable Aβ42 (P = .01) values were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (P = .01) and decreasing/relatively stable plasma Aβ42 (P = .01) was associated with faster cognitive decline, primarily in memory., Conclusions: The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia.

The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL; and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-2'deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells., Competing Interests: The authors have declared that no competing interests exist.

Recent studies have demonstrated that cholesterol metabolism has an important role in Alzheimer's disease (AD) pathogenesis, suggesting that cholesterol-related genes may be significant genetic risk factors for AD. Based on the results of genome-wide screens, along with biological studies, we selected three genes as candidates for AD risk factors: ATP-binding cassette transporter A1 (ABCA1), cholesterol 25-hydroxylase (CH25H) and cholesterol 24-hydroxylase (CH24H). Case-control of North American Caucasians and AD families of Caribbean Hispanic origin were examined. Although excellent biological candidates, the case-control dataset did not support the hypothesis that these three genes were associated with susceptibility to AD. Similarly, no association was found in the Caribbean Hispanic families for CH25H. However, we did observe a possible interaction between ABCA1 and APOE in the Hispanics.

Background: The p73 protein, a paralogue of the p53 tumor suppressor, is essential for normal development and survival of neurons. TP73 is therefore of interest as a candidate gene for Alzheimer's disease (AD) susceptibility. TP73 mRNA is transcribed from three promoters, termed P1-P3, and there is evidence for an additional complexity in its regulation, namely, a variable allelic expression bias in some human tissues., Methods: We utilized RT-PCR/RFLP and direct cDNA sequencing to measure allele-specific expression of TP73 mRNA, SNP genotyping to assess genetic associations with AD, and promoter-reporter assays to assess allele-specific TP73 promoter activity., Results: Using a coding-neutral BanI polymorphism in TP73 exon 5 as an allelic marker, we found a pronounced allelic expression bias in one adult brain hippocampus, while 3 other brains (two adult; one fetal) showed approximately equal expression from both alleles. In a tri-ethnic elderly population of African-Americans, Caribbean Hispanics and Caucasians, a G/A single nucleotide polymorphism (SNP) at -386 in the TP73 P3 promoter was weakly but significantly associated with AD (crude O.R. for AD given any -386G allele 1.7; C.I. 1.2-2.5; after adjusting for age and education O.R. 1.5; C.I. 1.1-2.3, N= 1191). The frequency of the -386G allele varied by ethnicity and was highest in African-Americans and lowest in Caucasians. No significant differences in basal P3 promoter activity were detected comparing -386G vs. -386A promoter-luciferase constructs in human SK-NSH-N neuroblastoma cells., Conclusions: There is a reproducible allelic expression bias in mRNA expression from the TP73 gene in some, though not all, adult human brains, and inter-individual variation in regulatory sequences of the TP73 locus may affect susceptibility to AD. However, additional studies will be necessary to exclude genetic admixture as an alternative explanation for the observed associations.

Background: Missense mutations in the amyloid precursor protein (APP) gene cause early-onset Alzheimer disease (AD). However, little is known regarding the effects of polymorphisms in regulatory sequences of APP on AD susceptibility., Objectives: To identify polymorphisms in the APP promoter, to test these for associations with AD, and to assess their influence on APP promoter activity in transfected cells., Setting: Community study of 1013 people of white, African American, or Caribbean Hispanic ethnicity, 65 years and older, residing in northern Manhattan., Main Outcome Measures: The diagnosis of AD was established by stringent criteria, with multiple follow-up examinations over 7 years., Results: We identified 2 polymorphisms in the APP promoter: a rare G-->C variant at -9 and a frequent G-->C variant at +37 relative to the transcription start site. The +37C allele was most frequent in African American patients (18% frequency), followed by Caribbean Hispanic patients (10%) and white patients of European descent (3%). This allele was overrepresented among patients with AD compared with elderly controls (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.08-2.27 in the combined ethnic groups), but this was not significant after adjusting for age, sex, and education (OR, 1.41; 95% CI, 0.93-2.12). A stronger association was found in participants lacking any apolipoprotein-E epsilon4 allele (OR, 2.12; 95% CI, 1.36-3.32 [univariate analysis]; OR, 2.08; 95% CI, 1.26-3.45 after adjusting for age, sex, and education). The -9C allele was not frequent enough to be evaluated for a disease association. Both variants were tested in promoter-reporter assays in U-87 glioma cells, and no differences in promoter activity were detected., Conclusions: The -9G/C and +37G/C APP promoter polymorphisms are unlikely to contribute strongly to AD susceptibility or to cause major differences in APP expression, but the +37C allele warrants further study for association with AD in larger population samples.

To assess the relationship of longitudinal brain magnetic resonance imaging (MRI) and infection with human immunodeficiency virus (HIV), a cohort of HIV+ and HIV&#8722; gay men and injection drug users (IDU) were evaluated prospectively. Subjects underwent two evaluations including MRI scans, neurologic examinations, neuropsychological assessments and lymphocyte subset determinations one year apart. MRI changes over a one year period were analyzed with respect to serostatus, risk group, CD4 counts, neurological findings and neuropsychological performance. The frequency of MRI changes was no different in subjects with or without HIV infection and no new opportunistic infections or neoplasms were seen. However, among HIV+ subjects with CD4 count < 200 at the time of the initial scan, an increase in white matter hyperintensities was significantly more common. Also among HIV+ subjects, atrophy increased in association with declining CD4 count. Finally, subjects who developed significant neurologic deterioration in one year were much more likely to have increased atrophy. These results suggest that while there are morphological brain changes associated with HIV infection, they are most often seen in association with immunologic or neurologic deterioration.