Physical Activity Moderates the Relationship between Cardiovascular Disease Risk Burden and Cognition in Older Adults.

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.

Sex-specific genetic architecture of late-life memory performance.

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 (Nmales  = 11,942; Nfemales  = 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.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

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.

Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans.

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.

Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets.

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.

Association of Life's Simple 7 with incident dementia and its modification by the apolipoprotein E genotype.

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.

Reproducibility of serum cytokines in an elderly population.

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-1ß, 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.

Analysis of pedigree data in populations with multiple ancestries: Strategies for dealing with admixture in Caribbean Hispanic families from the ADSP.

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.

Distinct cytokine profiles in human brains resilient to Alzheimer's pathology.

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-1ß, 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.

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

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 ptau181-Aß42 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.

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study.

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.

Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.

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.

Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

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.

Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease.

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_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.

Inbreeding among Caribbean Hispanics from the Dominican Republic and its effects on risk of Alzheimer disease.

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.

Human whole-exome genotype data for Alzheimer's disease.

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.

Altered DNA methylation in leukocytes with trisomy 21.

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.

Association of Subjective Cognitive Decline With Progression to Dementia in a Cognitively Unimpaired Multiracial Community Sample.

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.

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.

Alzheimer's disease (AD) heritability is enriched in glial genes, but how and when cell-type-specific genetic risk contributes to AD remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets. In an autopsy dataset spanning all stages of AD (n=1,457), astrocytic (Ast) ADPRS was associated with both diffuse and neuritic Aß plaques, while microglial (Mic) ADPRS was associated with neuritic Aß plaques, microglial activation, tau, and cognitive decline. Causal modeling analyses further clarified these relationships. In an independent neuroimaging dataset of cognitively unimpaired elderly (n=2,921), Ast-ADPRS were associated with Aß, and Mic-ADPRS was associated with Aß and tau, showing a consistent pattern with the autopsy dataset. Oligodendrocytic and excitatory neuronal ADPRSs were associated with tau, but only in the autopsy dataset including symptomatic AD cases. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.

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-ß), 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-ß, and microglial ADPRS was associated with amyloid-ß 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.