BACKGROUND:The Alzheimer's Disease Sequencing Project Gene Verification Committee developed a systematic framework to adjudicate genetic evidence for AD and related dementias, addressing wide variation in association quality. METHODS:Phase 1 established tiered criteria by evaluating 23 nominated loci across study designs. Phase 2 applied this framework to 29 large-scale genome-wide studies published since 2015, tiering 163 unique loci. RESULTS:Phase 1 yielded 17 high-confidence loci (12 linked to specific genes), and Phase 2 identified 111 high-confidence loci/genes with replicated associations across ancestries and convergent single-variant/variant-set evidence. Prioritized loci highlight APP processing, microglial immunity, and lipid metabolism pathways, including genes not captured by existing resources like Agora or Open Targets. Summarized results can be viewed at https://topgenes.niagads.org/. CONCLUSION:This rigorously adjudicated catalog represents the most comprehensive AD/ADRD genetics resource to date, providing a foundation for functional validation and therapeutic discovery with broad applicability to complex diseases.

Histopathological assessment has served as the gold standard for diagnosing Alzheimer's disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10-11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10-10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10-201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10-8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10-8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10-7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.

Background:Sequence-to-function (S2F) deep learning models are increasingly used to prioritize non-coding regulatory variants, but their behavior across ancestrally diverse populations remains unclear. Because both training data and reference resources are heavily European-centered, multi-ancestry benchmarks are needed to determine whether S2F scores capture regulatory effects consistently across populations with different allele-frequency and LD patterns. Methods:We evaluated Borzoi and AlphaGenome using whole blood eQTL data from the MAGENTA cohort, including African American (AA; N = 224), Caribbean Hispanic (CH; N = 209), and Non-Hispanic White (NHW; N = 235) participants. Model predictions were benchmarked against sampled nominal eQTLs and ancestry-stratified SuSiE fine-mapped variants using Spearman correlation, direction concordance, inter-model convergence, and distance-matched AUROC, with sensitivity analyses for minor allele frequency and comparison-set definition. We also compared FILER functional annotation overlap among high-Posterior Inclusion Probability (PIP) variants across ancestries. Results:Both models showed weak agreement with nominal eQTL effect sizes across ancestries and TSS-distance bins (ρ ≤ 0.138), with direction concordance only marginally above chance. Agreement and discrimination improved for high-confidence fine-mapped variants, and Borzoi and AlphaGenome showed stronger inter-model convergence on fine-mapped variants than on nominal eQTLs, consistent with enrichment for regulatory variants whose effects are more apparent to sequence-based models. In distance-matched AUROC analyses at PIP ≥ 0.9 using PIP < 0.01 variants as low-PIP comparison variants, the AA high-PIP variant set yielded the highest discrimination for both Borzoi (0.837 [95% CI: 0.790-0.870]) and AlphaGenome (0.820 [0.793-0.845]). The CH-versus-NHW ordering was model-dependent: Borzoi yielded higher AUROC in NHW than CH, whereas AlphaGenome produced nearly identical CH and NHW estimates. AUROC values were lower when intermediate-PIP variants were used as comparison variants, but the AA set retained the highest discrimination. MAF-stratified sensitivity analyses attenuated some ancestry contrasts but did not eliminate the higher AA discrimination pattern. Functional annotation analysis showed that AA high-PIP variants more often overlapped chromatin accessibility and chromatin-contact annotations than NHW variants, despite lower overlap with prior eQTL and sQTL annotation catalogs. Conclusions:Borzoi and AlphaGenome showed limited agreement with nominal eQTL effect sizes, but better distinguished high-confidence fine-mapped eQTLs from low-PIP variants. These results support using S2F scores as prioritization evidence for fine-mapped regulatory variants, especially promoter-proximal high-PIP variants, rather than as standalone predictors of eQTL effect size. The strongest discrimination was observed for the AA high-PIP variant set. Overall, the AA result is best interpreted as stronger separation of high-PIP variants from lower-PIP comparison variants, shaped by fine-mapping resolution, LD, the choice of comparison variants, and annotation composition.

INTRODUCTION:Little is known about genetic risk factors for dementia in South Asians. Examining genetic variants that occur at higher frequency in India compared to other ancestries (i.e., Indian enriched variants) may identify genetic associations with cognitive function that are potentially unique to the Indian population. METHODS:We examined whether 3.43 million variants enriched in India compared to European (EA), East Asian (EAS), and African (AFR) ancestries were associated with seven measures of cognitive function in 2680 older adults from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). RESULTS:Identified Indian-enriched variants were largely near loci previously associated with neuropsychiatric traits, N-acetyltaurine levels, educational attainment, and cardiovascular risk factors for dementia. Several variants near genes previously associated with intellectual disabilities and synaptic function exhibited sex-specific effects. DISCUSSION:Indian-enriched variants may play a significant role in cognitive function in South Asians living in India. HIGHLIGHTS:Some cognitive function-associated variants are unique to, or more common in, India. Implicated genes were in cardiovascular, neurocognitive, and inflammatory pathways. Some Indian-enriched genetic variants demonstrate sex-specific effects.

Fourteen years ago, Alzheimer’s disease (AD) genetics entered an era of exponential data growth, but the infrastructure to support and steward that data had yet to catch up. Large-scale genomic discovery demands more than storage; it requires coordination, ethical rigor, and a platform architecture that transforms raw data into shared knowledge. In response, the National Institute on Aging launched the Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), not simply to house genetic data for AD and AD-related dementias (ADRD), but to enable its responsible reuse. What began in 2012 as a repository has evolved into an integrated system for policy-aligned access, harmonized data production, and broad community engagement. A detailed overview of NIAGADS was recently published as a Perspective in Alzheimer’s & Dementia1. In this Commentary, we reflect on key lessons from building and operating NIAGADS at national scale, with the goal of informing the next generation of genomic platforms.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer’s disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer’s Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long (TL > 0) and short (TL ≤ 0) groups. An AD GWAS for the interaction of TL with variants having a minor allele count > 20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP × TL interaction term. AD risk was associated with shorter TL (β = -0.48, P < 2 × 10–16). Longer and shorter TL were associated with dosages of APOE ε2 (P = 3.40 × 10–4) and ε4 (P = 7.05 × 10–3), respectively. In the EA group, genome-wide significant (GWS) TL × SNP interactions were identified for variants in SEMA6A (P = 1.42 × 10–8) and LOC105378654 (P = 4.17 × 10–8), between IL15 and INPP4B (P = 1.77 × 10–8) and upstream of RP11-2N5.2 (P = 4.60 × 10–8). In the NAH group, GWS interactions were observed with an intronic variant in BSN (P = 3.26 × 10–8) and missense variant in MST1 (P = 3.26 × 10–8). In the total sample, interactions with variants between CTD-2160D9.1 and EEF1A1P20 (P < 1.19 × 10–8), in TBC1D22A (P = 1.06 × 10–8) and in PLK1 (P = 3.28 × 10–8) were GWS. We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis.

INTRODUCTION Herpes simplex virus-1 (HSV-1) has been implicated in Alzheimer disease (AD). METHODS Reads from Alzheimer’s Disease Sequencing Project whole-genome sequencing data collected from brain (2,203 AD; 616 controls) and blood (8,908 AD; 15,768 controls) were aligned to viral genomes. Generalized linear mixed-models tested for the effect of HSV-1 DNA on AD, and we performed GWAS on HSV-1 presence and SNP×HSV-1 interaction effects on AD, adjusting for age, sex, tissue, library preparation, relatedness, and ancestry principal components. RESULTS Across ancestry groups, HSV-1 DNA was consistently less frequent in AD cases; reads predominantly mapped to regions containing the latency-associated transcript region. DNA prevalence was lower in APOE -ε4 carriers; HSV-1 was associated with reduced AD risk in ε4 non-carriers but increased risk in carriers. GWAS identified host genetic influences on HSV-1 detection and interaction loci affecting AD risk. DISCUSSION HSV-1 DNA showed an inverse association with AD and is affected by genetics.

We previously published a sex-specific genetic analysis of memory performance, a strong endophenotype of Alzheimer's disease (AD), whereby we identified numerous sex-specific genetic loci, candidate genes, and biological pathways associated with late-life memory performance. Here, we expand on this work by conducting a sex-specific, cross-ancestral genetic analysis of three cognitive domains related to cognitive change in AD: memory, executive functioning, and language. This analysis was comprised of 10 aging and AD cohorts, including 33,918 older adults with a mean age of 73 years old, 57% females and 59% cognitively unimpaired. First, we evaluated SNP-based heritability across all three cognitive domains, both with baseline performance and longitudinal cognitive decline, and determined that the heritability across all measures was comparable across sexes. Next, we conducted cross-ancestry, genome-wide meta-analyses across the 10 cohorts, identifying three novel genome-wide significant loci relating to cognition in a sex-specific manner. First, we identified a locus (rs13387871), associated with female-specific language decline, and functional annotation suggested VRK2 as a candidate gene of interest; VRK2 is a published candidate gene for multiple neuropsychiatric traits, especially those involving language ability. Then we identified two sex-specific loci among individuals with cognitive impairment. The first locus was associated with male-specific memory decline (rs12501200), and functional annotation suggested DCHS2 as a gene of interest; notably DCHS2 is a published candidate gene for AD age-at-onset and tau pathology burden. Finally, among cognitively impaired individuals, we identified a sex-interaction with baseline executive functioning (rs1380012), and functional annotation suggested AGA as a candidate gene of interest. We additionally identified numerous biological pathways associated with sex-specific AD-related cognitive performance, including regulation of meiosis, fatty acid synthesis, and chromatin silencing. Our comprehensive genetic analysis of memory, executive functioning, and language performance highlighted genetic loci, genes, and biological pathways that relate to sex-specific cognitive change in both preclinical and clinical AD.

BackgroundAlzheimer’s disease (AD) and related dementias are a growing health and economic burden in India. Blood levels of amyloid beta (Ab), tau, and other proteins marking neuronal injury are biomarkers of AD risk and are potentially important for AD prevention.MethodsIn 2,224 participants from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD), we performed gene-based analyses on (1) missense/loss-of-function (LoF) single-nucleotide variants (SNVs) and (2) brain-specific promoter/enhancer SNVs across 84 genes selected from AD GWAS and 25 gene-biomarker pairs selected from biomarker GWAS. We used variant-Set Test for Association using Annotation infoRmation (STAAR) across 7 neurodegenerative biomarkers measured in blood: Ab40, Ab42, Ab42/Ab40, total tau (tTau), tau phosphorylated at threonine 181 (pTau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). We adjusted for age, sex, and genetic ancestry, with random intercepts for genetic relatedness and biomarker plate. Analyses incorporated weighted annotation scores (e.g., deleteriousness). Significant results (FDR-q < 0.1) were followed up with single variant analysis. Genes were also assessed for sex- and age-interactions using iSKAT.ResultsMissense/LoF variants in 6 AD-associated genes (ECHDC3, CLU, APOE, EPHA1, ICA1L, CASS4) and 1 biomarker-associated gene (APOE) were associated with Ab40, Ab42/Ab40, pTau, and/or GFAP (FDR q < 0.1), with the most significant SNVs tending to be rare/low-frequency (MAF ≤ 0.05) and potentially deleterious. Promoter/enhancer variants in 1 AD-associated gene (CCDC6) were associated with Ab42/Ab40, with the index SNV being a potentially deleterious common variant (MAF = 0.27). Several associated variants appeared to have higher frequency in India compared to other global populations. Missense/LoF SNVs in two AD genes (EPHA1, MS4A6A) had sex-specific effects on Ab42 and/or tTau, and promoter/enhancer SNVs in four AD genes (DGKQ, MS4A6A, MS4A4A, JAZF1) had sex-specific effects on tTau and/or pTau. Missense variants in 12 AD genes and promoter/enhancer variants in two AD genes showed interaction with age on at least one biomarker, primarily GFAP and NfL with genetic effects tending to be stronger at older ages.ConclusionRare and common variants in AD- and neurodegenerative biomarker-associated genes with increased frequency in India compared to other populations may impact blood levels of neurodegenerative biomarkers in South Asians.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

INTRODUCTION:We utilized an Alzheimer's disease (AD) polygenic risk score (PRS) to discover associations with novel rare variants (RVs). METHODS:PRSs for European ancestry (EA) participants of the Alzheimer's Disease Sequencing Project were calculated using summary statistics from a large genome-wide association study. Participants were classified into high (n = 5738) and low (n = 5324) PRS groups based on the median PRS and on the lower and upper 35% of the PRS distribution. RESULTS:Risk variants were disproportionately enriched in the low-PRS group, while protective ones were disproportionately enriched in the high-PRS group. Genome-wide significant (GWS) associations for increased AD risk were identified with RVs spanning a 3.5-Mb region on chromosome 14. GWS protective variants in ALDH9A1, BICC1, and PAN3 were identified in the upper 35% PRS group. CONCLUSION:Our findings provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.

India is the most populous country globally, yet genetic studies involving Indian individuals remain limited. The Indian population is composed of many founder groups and has a mixed genetic ancestry, including an ancestral component not observed anywhere outside of India. This presents a unique opportunity to uncover novel disease variants and develop tailored medical interventions. To facilitate genetic research in India, a crucial first step is to create a foundational resource that serves as a benchmark for future population studies and methods development. Thus, we constructed the largest and most nationally representative linkage disequilibrium (LD) and genotype imputation reference panels in India to date, using high-coverage whole-genome sequencing data of 2,680 participants from the Longitudinal Aging Study in India-Harmonized Diagnostic Assessment of Dementia (LASI-DAD). As an LD reference panel, LASI-DAD includes 69.5 million variants, representing 170% and 213% increases relative to the 1000 Genomes Project and TOP-LD South Asian panels, respectively. Besides serving as an LD lookup panel, LASI-DAD facilitates various statistical analyses relying on precise LD estimates. In polygenic risk score (PRS) analyses, LASI-DAD improved the PRS predictive performance by 2.1%-35.1% across traits and studies. As an imputation reference panel, LASI-DAD enhanced imputation accuracy, measured by the Pearson correlation between imputed and true genotypes, by 3%-101% (mean 38%) compared with the TOPMed panel and by 3%-73% (mean 27%) compared with the Genome Asia Pilot panel across different allele frequencies. The LASI-DAD reference panel is publicly available to benefit future studies.

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia. Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10-21, odds ratio 26.7). When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A. We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis.

APOE’s ε4 haplotype (APOE4) is late onset Alzheimer’s disease’s (LOAD) strongest genetic risk factor. Therefore, accurately modeling APOE4’s effect is critical to understanding LOAD. This is especially important as APOE4 odds ratios (OR) vary across racial and ethnic (R/E) groups. We analyzed the APOE4-LOAD association in 3,196 East Asian, 31,105 non-Hispanic White (White), 1,646 Hispanic and Latino (Hispanic), and 6,068 non-Hispanic Black (Black) participants using three genetic models: additive, genotypic, and a reparametrized model accounting for deviations from additivity (DA). Each model adjusted for age, sex, and genetic ancestry. We first calculated additive APOE4 ORs in each R/E group, finding East Asian participants had the largest APOE4 ORs (ORAPOE4: 5.2, 95

Pathway-specific polygenic risk scores (pathway-PRS) measure aggregate risk across single nucleotide variants (SNPs) annotated to pathway genes. In most applications, SNP-to-gene annotation is based on SNP proximity to gene boundaries. This approach is ill-suited for incorporating non-coding SNPs, which can regulate gene expression over long distances and represent a large proportion of risk variants in complex diseases, such as Alzheimer's disease (AD). AD therefore provides a useful setting for evaluating whether functionally informed SNP-to-gene annotation improves pathway-PRS construction. Here, we compare AD pathway-PRS performance across annotation strategies that integrate varying levels of functional genomic data, including adult brain chromatin interaction and expression quantitative trait loci (eQTL) data. In the UK Biobank (n=328,526), including AD cases defined by ICD-9/10 codes (n=3,043) and family history of AD/dementia (n=38,589), the strategy integrating chromatin interaction and eQTL data consistently improves pathway-PRS performance. We replicate this finding in independent Alzheimer's Disease Genetics Consortium data (n=3,370). We further observe that pathway-PRS associations with AD vary by annotation strategy and that integrative annotation increases power to detect sex-dependent and age-at-onset associations. Together, these findings support the use of functionally informed SNP-to-gene annotation for pathway-PRS construction and highlight the importance of applying multiple annotation strategies for robust inference.

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:Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. RESULTS:We found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. CONCLUSIONS:The copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer's disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes. Genome-wide meta-analyses identified three novel loci: a female-specific language decline-associated locus, VRK2 (rs13387871), which is a published candidate for neuropsychiatric traits involving language ability; a male-specific memory decline-associated locus among cognitive impaired, DCHS2 (rs12501200), which is a published candidate gene for AD age-at-onset; and a sex-interaction with baseline executive functioning, AGA (rs1380012), among cognitive impaired. We additionally provide evidence for shared genetic architecture between lifetime estrogen exposure and AD-related cognitive decline. Overall, we identified sex-specific variants, genes, and pathways relating to three cognitive domains among older adults.

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-FUS), and the current phase, ADSP-FUS 2.0: The Diverse Population Initiative, focusing on whole genome sequencing (WGS) of non-European populations including Hispanic/Latino (HL), non-Hispanic Black with African Ancestry (NHB-AA) and Asian populations. Support for these efforts include newly funded initiatives such as The DAWN Project, focused on recruitment of African, African-American and Hispanic American populations, and the Asian Cohort for Alzheimer’s Disease (ACAD). ADSP cohorts consist of studies of AD, dementia, and age-related conditions. Clinical classifications are assigned based on standard criteria and derived from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, APOE genotyping is available for all ADSP samples. The ADSP currently consists of 40 cohorts comprised of ∼36,300 individuals, with plans to sequence >110,000 individuals from diverse race/ethnicity. Genotyping, sequencing, and clinical adjudication has been performed on 36,361 participants (cases N = 12,133, median age = 72; cognitively-unimpaired(CU) individuals N = 17,116, median age = 74; ADRD N = 7,112, median age = 71). Mean ages for cases and controls vary across cohorts, 57.0+5.6 to 86.5+4.2 cases and 63.3+7.8 to 90.0+0 controls. 61% participants female, distributed as follows: cases(60.3%), CU(63.7%), and ADRD(55.8%). APOE genotype proportions differ considerably across reported race/ethnicity, for example highest for APOE ε 4/ ε 4 carriers observed in Non-Hispanic whites participants (7.4%) and the lowest in Asians (1.7%) The results provide an overview of clinical features in ADSP cohorts. The growth of the ADSP-FUS 2.0 is central to the ADSP and expanding the size and diversity of this genomic resource available via NIAGADS. WGS data will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP-FUS 2.0 will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective.

INTRODUCTION:Most genetic studies for Alzheimer's disease (AD) have been focused on late-onset AD (LOAD). There are no large genetic studies on early-onset AD (EOAD). METHODS:We performed a multi-ancestry (non-Hispanic European, African, and East Asian) genome-wide association study (GWAS) including a total of 7,349 cases and 17,887 control. Cases with age at onset younger than 70 years were included. Sensitivity analysis including cases with onset <65 was performed. Only controls older than 70 were included to decrease the risk of developing LOAD. RESULTS:We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and functional annotations, we nominate eight novel genes that are involved in microglia activation, glutamate production, and signaling pathways. DISCUSSION:EOAD, although sharing genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification. HIGHLIGHTS:We performed the largest and first multi-ethnic genetic screening for early-onset Alzheimer's disease (AD). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. The novel genes are implicated microglia activation, glutamate production, and signaling pathways. EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.