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.

Cerebral amyloid angiopathy impacts neurofibrillary tangle burden and cognition.

Cerebral amyloid angiopathy commonly co-occurs with amyloid β plaques and neurofibrillary degeneration and is proposed to contribute to cognitive impairment. However, the interplay among these pathologic changes of Alzheimer disease is not well understood. Here we replicate and extend findings of a recent study that suggested the association of cerebral amyloid angiopathy and cognitive impairment is mediated by neurofibrillary degeneration.

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.

NIAGADS: A Comprehensive National Data Repository for Alzheimer's Disease and Related Dementia Genetics and Genomics Research.

NIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer's Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples.

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored.

Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates at the locus.

Late-onset Alzheimer's disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, including , , and .

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 approximately 7.4% in those 60 years and older, yet little is known about genetic risk factors for dementia in this population. Most known risk loci for Alzheimer's disease (AD) have been identified from studies conducted in European Ancestry (EA) but are unknown in South Asians.

Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry.

Introduction: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts.

Methods: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses.

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

Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO).

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV.

Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.

MitoH3: Mitochondrial Haplogroup and Homoplasmic/Heteroplasmic Variant Calling Pipeline for Alzheimer's Disease Sequencing Project.

Background: Mitochondrial DNA (mtDNA) is a double-stranded circular DNA and has multiple copies in each cell. Excess heteroplasmy, the coexistence of distinct variants in copies of mtDNA within a cell, may lead to mitochondrial impairments. Accurate determination of heteroplasmy in whole-genome sequencing (WGS) data has posed a significant challenge because mitochondria carrying heteroplasmic variants cannot be distinguished during library preparation.

MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons.

Inclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer's disease (AD). The spreading of misfolded tau "seeds" along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and Sub-haplotypes.

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.

A comparative study of structural variant calling in WGS from Alzheimer's disease families.

Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines, Scalpel and Parliament, for SV/indel calling, we assessed sensitivity through sample replicates (N = 9) with in silico variant spike-ins.

50,000 years of Evolutionary History of India: Insights from ~2,700 Whole Genome Sequences.

India has been underrepresented in whole genome sequencing studies. We generated 2,762 high coverage genomes from India-including individuals from most geographic regions, speakers of all major languages, and tribal and caste groups-providing a comprehensive survey of genetic variation in India. With these data, we reconstruct the evolutionary history of India through space and time at fine scales.

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 approximately 7.4% in those 60 years and older, yet little is known about genetic risk factors for dementia in this population. Most known risk loci for Alzheimer's disease (AD) have been identified from studies conducted in European Ancestry (EA) but are unknown in South Asians.

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.