Examining the Performance of Polygenic Risk Scores for Alzheimer Disease Within and Across Populations Using -Fold Cross-Validation.

Background And Objectives: Alzheimer disease (AD) has a complex etiology with a strong genetic component. Despite mounting evidence that genetic risk effect sizes vary by population, most research on the genetics of AD has examined only data sets of individuals with European ancestry. In this study, we investigate the variable performance and transferability of polygenic risk scores (PRSs) by deriving a PRS from analyses of AD for various race and ethnic categories and applying this across groups using a -fold cross-validation approach.

A specialized reference panel with structural variants integration for improving genotype imputation in Alzheimer disease and related dementias.

We developed an imputation panel for Alzheimer disease (AD) and related dementias (ADRD) using 15,958 whole-genome sequencing (WGS) samples from the Alzheimer Disease Sequencing Project. Recognizing the importance of associations between structural variants (SVs) and AD and their underrepresentation in existing public reference panels, our panel uniquely integrates single-nucleotide variants (SNVs), short insertions or deletions (indels), and SVs. This panel enhances the imputation of rare variants underlying disease susceptibility onto genotype array data, offering a cost-effective alternative to WGS while significantly augmenting statistical power.

Genome-wide association studies of Alzheimer's disease and related disorders stratified by sex, onset age, and Apolipoprotein E genotype reveal novel risk loci in African Americans.

Background: Alzheimer's disease (AD) risk variants have been identified in European ancestry cohorts that have stronger effects at certain ages, in individuals with a specific sex, or in those with specific isoforms of APOE, the strongest AD risk locus. However, sample sizes in African ancestry (AA) cohorts have been underpowered to perform stratified analyses.

Methods: We generated genome-wide association study datasets stratified by sex, age at onset (< 75 vs ≥ 75), and APOE-ε4 carrier status in AA cohorts from MVP and the Alzheimer's Disease Genetics Consortium (ADGC).

Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores.

Alzheimer disease (AD) polygenic risk scores (ADPRS) built from cell-type (ct) specific genetic variants can be used to infer cell-type contributions to AD. We derived two ct-ADPRSs using variants near single-nuclei RNA-seq (snRNA) derived cell-type specific genes or on single-nuclei ATAC-seq (snATAC) derived cell-type specific accessible chromatin regions. We generated a multi-omic ct-ADPRS for eight neuron subtypes using both single-nuclei datasets.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

Background: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.

Results: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.

Integrated genomic analysis and CRISPRi implicates in Alzheimer's disease risk.

Genome-wide association studies (GWAS) have identified numerous loci linked to late-onset Alzheimer's disease (LOAD), but the pan-brain regional effects of these loci remain largely uncharacterized. To address this, we systematically analyzed all LOAD-associated regions reported by Bellenguez et al. using the FILER functional genomics catalog across 174 datasets, including enhancers, transcription factors, and quantitative trait loci.

A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India.

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 more tailored medical interventions.

50,000 years of evolutionary history of India: Impact on health and disease variation.

India has been underrepresented in genomic surveys. We generated whole-genome sequences from 2,762 individuals in India, capturing the genetic diversity across most geographic regions, linguistic groups, and historically underrepresented communities. We find most Indians harbor ancestry primarily from three ancestral groups: South Asian hunter-gatherers, Eurasian Steppe pastoralists, and Neolithic farmers related to Iranian and Central Asian cultures.

Region-Based Analysis with Functional Annotation Identifies Genes Associated with Cognitive Function in South Asians from India.

The prevalence of dementia among South Asians across India is high among those who are 65 years and older, yet little is known about genetic risk factors for dementia in this population. Using whole-genome sequence data from 2680 participants from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD), we performed a gene-based analysis on the missense/loss-of-function (LoF) and brain-specific promoter/enhancer variants of 84 genes, previously associated with AD in European Ancestry (EA). These analyses were performed separately, both with and without incorporating additional annotation weights (e.

Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways.

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.

Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries.

Structural variation detection and association analysis of whole-genome-sequence data from 16,543 Alzheimer's disease sequencing project subjects.

Introduction: The role of structural variations (SVs) in Alzheimer's disease (AD) remains understudied.

Methods: We analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (N = 16,543) and identified 400,234 (168,223 high-quality) SVs. Laboratory validation yielded a sensitivity of 82% (85% for high-quality).

Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults.

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.

Alzheimer's Disease Sequencing Project release 4 whole genome sequencing dataset.

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 Disease (GCAD) uniformly processed WGS from 36,361 ADSP samples, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4).

Results: This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 6.

Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease.

Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis.

Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.

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.

Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures.

Background: Genome-wide association studies (GWAS) have identified over 1,000 blood pressure (BP) loci and over 80 loci for Alzheimer's disease (AD). Considering BP is an AD risk factor, identifying pleiotropy in BP and cognitive performance measures may indicate mechanistic links between BP and AD.

Methods: Genome-wide scans for pleiotropy in BP variables-systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse pressure (PP)-and co-calibrated scores for cognitive domains (executive function, language, and memory) were performed using generalized linear mixed models and 116,075 longitudinal measures from 25,726 participants of clinic-based and prospective cohorts.

Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer's disease.

Studies of the genetics of Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most of the disease heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms of genetic variation. There are over one million short tandem repeats (STRs) in the genome, and their link to AD risk has not been assessed.

Alzheimer's Disease Sequencing Project Release 4 Whole Genome Sequencing Dataset.

The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's Disease and Related Dementias (AD/ADRD) by sequencing whole genomes of affected participants and age-matched cognitive controls from diverse populations. The Genome Center for Alzheimer's Disease (GCAD) processed whole-genome sequencing data from 36,361 ADSP participants, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4). This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 2.

Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites.

Background: Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear.