Adam Naj

• PhD, Epidemiology
• University of Pennsylvania

INTRODUCTION The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's disease and related dementias (ADRD) by integrating whole genome sequencing (WGS) with other genetic, phenotypic, and harmonized datasets from diverse populations. METHODS The Genome Center for Alzheimer's D...

Background Genome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD), but their functional implications remain unclear. Transcriptome-wide association studies (TWAS) offer enhanced statistical power by analyzing genetic associations at the gene level rather than at the variant level, e...

Background The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). Objective To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. Methods Utilizin...

Background Recent Alzheimer’s disease (AD) genetics findings from genome-wide association studies (GWAS) span progressively larger and more diverse populations and outcomes. Currently, there is no up-to-date resource providing harmonized and searchable information on all AD genetic associations found by GWAS, nor linking the reported genetic varian...

Importance: SuperAgers are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts. Objective: To determine the frequency of APOE genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to...

Background The Apolipoprotein E ε4 (APOE‐ε4) allele is common in the population, but acts as the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE‐ε4 allele showing a s...

Background In this introductory talk, we embark on a journey of through the genomic frontiers of Alzheimer’s research via the revolutionary Alzheimer’s Disease Sequencing Project (ADSP). Method ADSP integrates together various components that collectively unravel the intricate genetic landscape of Alzheimer’s disease with the ultimate goal of adva...

Background The Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration and meta‐analysis of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data to facilitate the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated via the collabor...

Background NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer’s disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts...

Background Mosaic loss of the Y chromosome (LOY) is a somatic, age‐related event that has been previously associated with a variety of diseases of aging. A prior study of European cohorts demonstrated an association between LOY and Alzheimer’s Disease and more recent molecular studies have shown that LOY can also occur within microglia, suggesting...

Background The Alzheimer’s Disease Sequencing Project (ADSP) aims to identify genetic variation contributing to the development or protection of Alzheimer’s disease (AD) in diverse ancestral populations. The latest ADSP whole genome sequencing (WGS) data release includes over 36,000 individuals from 37 datasets (NIAGADS NG00067.v11 ADSP R4). Qualit...

Background Recent advances in Alzheimer’s Disease (AD) research have emphasized the importance of recruiting from diverse populations. Notably, African‐descent individuals have an almost doubled risk of developing AD compared to European‐descent individuals. Transcriptome‐wide association studies (TWAS) have advanced the analysis of non‐coding vari...

Background The ADSP is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD). Initial phases (Discovery and Discovery Extension) were predominantly non‐Hispanic Whites of European Ancestry (NHW‐EA). The ADSP expanded the population diversity in the Follow Up Study (ADSP...

Background While there are numerous genome‐wide association studies (GWAS) assessing the genetic basis of Alzheimer’s disease (AD), there are far fewer studies examining genetic factors for cognitive and global resilience to AD neuropathology. By focusing on a gene‐level rather than a single‐variant basis, transcriptome‐wide association studies (TW...

Background “SuperAgers” are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid‐60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle‐aged and older adults....

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-ge...

Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger m...

INTRODUCTION: Dementia is a multifactorial disease with Alzheimer’s disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 indi...

INTRODUCTION: Transcriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics from cis-eQTL meta-analyses and the largest clinically-adjudicated Alzheimer's Disease (AD) GWAS. METHODS: We...

Background The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer’s disease (AD). Objective To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods Using e...

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However,...

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 joi...

Background Apolipoprotein E4 (APOE4) is common in the population yet is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Here, we sought to identify genetic effects that differ by APOE4 genotype leveraging stratified and APOE interaction analyses. We hypothesized that we could identify novel genetic associations with longi...

Background A recently recognized subset of older individuals are an anomaly of cognitive decline; the “SuperAgers”, unsurprisingly named, achieve cognitive scores equivalent to much younger cognitively normal (CN) middle‐aged adults. Using longitudinal cognitive data harmonized across eight cohorts of aging and Alzheimer’s Dementia (AD), we investi...

Background Alzheimer’s disease (AD) is clinically characterized by disabling cognitive impairment, though substantial variability in cognitive symptoms and trajectories is observed in AD individuals. However, genetic predictors of domain‐specific cognitive performance remain undiscovered. We investigated cross‐sectional and longitudinal genetic arc...

Background Genetic analyses of cognitive endophenotypes have led to discoveries of novel loci contributing to Alzheimer’s disease (AD) risk. Sex differences are present in cognitive trajectories in aging and AD, and these may vary across cognitive domain. However, genetic drivers that may contribute to sex differences in cognitive trajectories have...

Background Lack of diversity in expanding genomic studies has limited the identification of LOAD risk variants that may be more prevalent in non‐European ancestry groups with more modest power requirements for detection. To help reverse this trend, we constructed and analyzed a multi‐ancestry collection of GWAS datasets in the Alzheimer’s Disease G...

Background Alzheimer’s disease and related dementias (ADRDs) are a group of complex neurodegenerative diseases and disorders that pose a growing global public health burden. Developing new treatments for ADRDs has been difficult and there is a pressing need for new therapeutic options. Drug repurposing, which involves finding new uses for existing...

Background Frontotemporal dementia (FTD) is a neurodegenerative syndrome characterized by distinct subtypes, each with unique clinical presentations and varying neuropathologic features. Although FTD is highly heritable, it is frequently undiagnosed and genetic causes of FTD are rarely determined, limiting what is known about the medical phenome as...

Background Genetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regi...

Background NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer’s disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts...

Background Previous whole exome sequencing (WES) studies of Alzheimer’s disease (AD) have identified genome‐wide significant associations with rare variants in several novel genes and highlighted the need for investigations in larger samples. We combined WES and whole genome sequencing (WGS) data assembled by the Alzheimer Disease Sequencing Projec...

Background By focusing on a gene‐level rather than a single‐variant basis, transcriptome‐wide association studies (TWAS) assess the role of genetically regulated gene expression in disease risk and improve statistical power by reducing the multiple testing burden by over a 100‐fold. A key limitation of current TWAS approaches is the requirement for...

Background Memory performance can serve as a strong endophenotype for Alzheimer’s disease (AD) that changes early and continues to decline with disease progression. Yet, the genetic architecture of memory is not well characterized in older adults. Here, we build on existing memory GWAS studies by performing predicted gene expression analysis (Predi...

Background Several studies have attempted to identify genes for age‐at‐onset (AAO) of Alzheimer’s disease (AD) through genome‐wide linkage and genome‐wide association studies (GWAS). While these efforts have thus far focused predominantly on non‐Hispanic white (NHW) populations, we present here the first GWAS to identify genetic contributors to AAO...

Background The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP beyond non‐Hispanic Whites of European Ancestry (NHW‐EA) populations. Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to whole genome sequence (WGS)...

Background The Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data with the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated through collaboration between investigators...

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). Le...

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 l...

Importance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective: To investigate whether sex and race modify APOE ε4 a...

Background The Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration and meta‐analysis of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data with the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated via the collaboration of...

Background Genome‐wide association studies (GWAS) for AD have identified numerous associated loci but have been focused only on the autosomes. We sought to identify novel AD‐associated genes on X‐Chromosome (X‐Chr). Method We evaluated the association of AD with X‐Chr variants in GWAS datasets assembled by the Alzheimer Disease Genetics Consortium...

Background Early Onset Alzheimer Disease (EOAD, age at onset [AAO] < = 65) is a severe form of AD, often occurring when patients are still caring for children or adults. Despite this, most genetic studies of EOAD have focused on autosomal dominant forms, and there is little understanding of similarities and differences between early and late onset...

Background The X chromosome is often omitted in disease association studies despite containing thousands of genes which may provide insight into well-known sex differences in the risk of Alzheimer’s Disease. Objective To model the expression of X chromosome genes and evaluate their impact on Alzheimer’s Disease risk in a sex-stratified manner. Me...

Background: Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. Methods: HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics...

Neurodegenerative pathologies consistent with Alzheimer’s disease (AD) are common in older adults even among those without cognitive symptoms. Genome‐wide association studies (GWAS) have identified loci associated with better‐than‐predicted cognitive performance for a given level of neuropathology, described as resilience to AD symptoms. Transcript...

Genetically regulated gene expression as assessed via Transcriptome‐wide association studies (TWAS) can be used to elucidate the mechanistic basis Alzheimer’s Disease. A limitation of current TWAS approaches is the requirement for individual‐level datasets with both genotypes and gene expression measures to produce effective prediction models. We s...

Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE) – the strongest risk gene for sporadic Alzheimer’s disease (AD). The HP gene has two functional alleles, HP2 and HP1, which contains a two‐exon deletion that changes its protein structure conformation. We hypothesize that this structural variation is associated with AD. To investigate th...

Increasing diversity in genomic studies is critical for defining the genetic architecture of LOAD by improving power to identify variants more prevalent in or specific to a given ancestry. In this study, we constructed and analyzed a multi‐ancestry collection of GWAS datasets in the Alzheimer’s Disease Genetics Consortium (ADGC) to identify novel L...

The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP Discovery and Discovery Extension cohorts beyond non‐Hispanic Whites of European Ancestry (NHW‐EA). Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to sequence...

Two‐thirds of Alzheimer’s disease (AD) patients are women and there are well‐established sex differences in the association between APOE and cognitive impairment in AD. However, it is not clear whether sex‐specific cognitive consequences of APOE emerge across all cognitive domains or in a domain‐specific manner. Data were obtained from 38,386 parti...

Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic eti...

Despite large genome‐wide association studies, only ∼30% of the heritability of Alzheimer’s disease is explained. The Alzheimer’s Disease Sequencing Project Whole Exome Sequencing (ADSP WES) has identified millions of genetic variants, over 97% of which are rare (MAF<1%), with 23% appearing in only one person. These rare variants could provide valu...

Alzheimer’s disease (AD) has high genetic heritability for both disease risk and age‐at‐onset (AAO) of AD. However, our understanding of genetics of AAO of AD lags behind AD risk. Here, we utilized two statistical approaches to identify genes modifying AAO of AD globally or in a sex‐specific manner. Pooled data from 9,219 AD cases and 10,345 contro...

NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer’s disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts for Heart...

Analysis of sex chromosomes is under‐reported in Alzheimer’s disease (AD) studies. As we gain more knowledge of disease associations and tissue‐specific regulatory effects of autosomal loci, there is a growing interest in building prediction models of gene expression in the brain to model the cumulative functions of non‐coding variants on the sex c...

Genome‐wide association studies (GWAS) have identified more than 40 genetic loci associated with Alzheimer’s disease (AD). Although vascular dementia (VaD) is the second most common type of dementia after AD, the genetic contribution to VaD is understudied. We hypothesize that common forms of dementia will share genetic risk factors. We conducted t...

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing d...

Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic ri...

Bigger sample size can help to identify new genetic variants contributing to an increased risk of developing Alzheimer’s disease. However, the heterogeneity of the whole-exome sequencing (WES) data generation methods presents a challenge to a joint analysis. Here we present a bioinformatics strategy for joint calling 20,504 WES samples collected ac...

Background: Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid-β (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. Methods: HP genotypes were imputed in 29 cohorts from the Alzheimer′s Disease (AD) Genetics...

Genetic heterogeneity describes the occurrence of the same or similar phenotypes through different genetic mechanisms in different individuals. Robustly characterizing and accounting for genetic heterogeneity is crucial to pursuing the goals of precision medicine, for discovering novel disease biomarkers, and for identifying targets for treatments....

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 ris...

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 ris...

Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated...

Over 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) Whole Exome Sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association betw...

Late-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic m...

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study res...

Background: We recently published a genome-wide association study (GWAS) for Alzheimer disease (AD) in African Americans (AA; 2,784 cases, 5,222 cognitively normal individuals) (Kunkle et al. JAMA Neurol. 2021). We now present a GWAS meta-analysis of this AA data stratified by APOEε4-genotype. Method: All datasets were imputed to the African Gen...

Background: Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer's Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating...

Background: The ADSP-FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late-onset Alzheimer Disease (LOAD). A concern in AD genetic studies is a lack of racial-ethnic diversity. The ADSP-FUS collects and sequences existing ethnically diverse and unique cohorts with clinical data t...

Background: The Alzheimer's Disease Variant Portal (ADVP, https://advp.niagads.org) is a curated and harmonized interactive platform providing the research community with a unified way to access and visualize the largest up-to-date collection of Alzheimer's disease (AD) genetic findings from >200 genome-wide association studies (GWASs). In this st...

Background: NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer's disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer's Disease Genetics Consortium (ADGC), Cohor...

Background: African Americans (AA) are substantially underrepresented in Alzheimer's disease (AD) genetic studies, yet their admixed genetic ancestry (African and European) provides a unique opportunity to identify novel genetic factors associated with AD related to genetic ancestry. Admixture mapping (AM) provides a more powerful approach than SN...

Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological change...

Over 90% of variants are rare, and 50% of them are singletons in the Alzheimer's Disease Sequencing Project Whole Exome Sequencing (ADSP WES) data. However, either single variant tests or unit-based tests are limited in the statistical power to detect the association between rare variants and phenotypes. To best utilize rare variants and investigat...

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study res...

Deeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer's disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed...

Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls i...

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we o...

Background Alzheimer’s disease (AD) genetic findings span progressively large genome‐wide association studies (GWASs) and meta‐analyses, with no single resource providing unified, searchable information on identified genetic variants and genes and supporting functional genomic evidence. We developed ADVP (Alzheimer’s Disease Variant Portal), a cura...

Background Recent meta‐analyses of genome‐wide association studies (GWAS) have identified ∼30 susceptibility LOAD loci in addition to APOE , however the majority are common variants (minor allele frequency (MAF)>0.02). We used the dense, high‐resolution Haplotype Reference Consortium (HRC) r1.1 reference panel (64,976 haplotypes/39,235,157 SNPs), w...

Background Genetic studies in Alzheimer disease (AD) are underrepresented in African‐descent populations. The African American (AA),population, with the admixed genetic ancestry (African and European) and high African ancestral background (∼80%), provides a unique opportunity to discover African ancestry‐specific genetic factors in AD. Admixture ma...

Background The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late‐onset Alzheimer Disease (LOAD). A major concern in AD genetic studies is a lack of racial‐ethnic diversity. The ADSP‐FUS collects and sequences existing both ethnically diverse and unique cohorts with extens...

Background The Alzheimer’s Disease Sequencing Project (ADSP) seeks to identify genomic variants contributing to increased risk of and/or protection from Alzheimer’s disease (AD) in multi‐ethnic populations. Here we report on statistical modeling considerations and results from 4707 diverse individuals including 2076 non‐Hispanic White, 1030 Black,...

Background NIAGADS is a national genetics data repository that facilitates access of genotypic data to qualified investigators for the study of the genetics of late‐onset Alzheimer’s disease (AD) and other neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts for H...

Background Recent work suggests unexplained heritability of Alzheimer’s Disease (AD) may involve rare variants in genes implicated in other neurodegenerative disorders. However, existing gene‐based tests have insufficient power to detect true associations when neutral variants are included. Therefore, identifying variants with potentially high impa...

Background Although stroke is an established risk factor for Alzheimer’s disease (AD), the role vascular factors play in driving AD remains uncertain. Here we leverage GWAS summary statistics to assess the genetic correlation (pleiotropy) between stroke and AD and introduce a novel fine‐mapping approach to pinpoint shared causal variants in the con...

Background Late‐Onset Alzheimer Disease (LOAD) is the most common neurodegenerative disease. Its heritability is estimated to be 40‐80%, yet the numerous genome‐wide studies (GWAS) conducted to date have identified risk variants that explain only ∼8% phenotypic variance. Method To improve understanding of the functional genetic etiology of LOAD, w...

Background Several studies have attempted to identify genes for age‐at‐onset (AAO) of dementia symptoms in Alzheimer’s disease (AD) through genome‐wide linkage (Daw et al. 1999, Li et al. 2002, Choi et al. 2011) and genome‐wide association studies (Kamboh et al. 2012, Naj et al. 2014). Naj et al. conducted a meta‐analysis of 14 datasets from the Al...

Background Using sequencing from multi‐ethnic AD studies, the ADSP aims to identify genomic variation contributing to elevated risk of, or protection from, AD. We examined coding region variation in the ADSP WES (whole exome sequencing) Release 2 dataset, comprising jointly‐called genotypes on 12,135 non‐Hispanic White (NHW), 4,108 African American...

Importance Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association...

Alzheimer’s Disease (AD) genetics has made substantial progress through genome-wide association studies (GWASs). An up-to-date resource providing harmonized, searchable information on AD genetic variants with linking to genes and supporting functional evidence is needed. We developed the Alzheimer’s Disease Variant Portal (ADVP), an extensive colle...