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Sex differences in progression and pathology of Alzheimer's disease (AD) suggest sex-specific factors influencing its development. While studies have established APOE-genotype as contributing to AD risk differently in men and women, few have searched for additional genetic sex differences in AD. To identify sex-specific AD genetic associations, we conducted genome-wide sex-aware meta-analyses in the Alzheimer's Disease Genetics Consortium (ADGC) and Alzheimer's Disease Sequencing Project (ADSP) datasets. Sex-interaction and sex-stratified analyses were performed in multi-ancestry genome-wide imputed AD datasets from the ADGC (N = 25,284 cases, 60% female and 33,455 controls, 63% female; ancestry/ethnicity distribution: 63.7% European, 15.6% African, 15.2% Hispanic/Latino, 5.5% Asian). STAAR aggregation-based rare-variant testing was also conducted in coding and non-coding genomic regions on an ancestrally diverse sample of 8,697 AD cases and 14,758 controls with whole-genome sequencing from the ADSP. Cross-ancestry sex-stratified analyses identified several loci with evidence of interaction (p <0.05) and suggestive significance in one sex (p <5x10-6) and not the other (p >0.05). These include male specific variants in STXBP6, MAP4K5 and the known AD locus PICALM. Genetic loci associated in females and not males include NPAS3, ZNF438 and a genome-wide result in NECTIN2 near the APOE locus. Top ancestry-specific results include associations at COL4A2 in Asian-ancestry males and C16orf96 in African-ancestry females. Cross-ancestry rare-variant aggregation-based testing revealed four novel genome-wide significant associations in females including with missense variants in SH3BP1. Five population specific associations were also discovered including with missense variants in SERTAD4 in a genetically-defined Hispanic/Amerindian/African ancestral population cluster and promoter variants of PSMA5 in a European population cluster. Seven male-specific effects were also discovered including genome-wide significant cross-ancestry associations with an enhancer region of MORC1 and a promoter of ITPKA. We identified sex-specific AD associations at loci with AD-relevant genes including STXBP6 (involved in AD relevant processes such as endolysosomal transport and synaptic transmission), NPAS3 (neurogenesis), COL4A2 (cerebral vasculature), ITPKA (learning/memory processes), PAQR3 (cholesterol homeostatis and neuronal function), and MORC1 (recently associated in a UK Biobank exome-wide sequencing study of dementia (Zhang et al. Alz & Dementia 2024). Understanding the nature of these associations could help explain sex differences in risk and progression for AD.

In May 2008, PulseNet detected a multistate outbreak of Salmonella enterica serotype Saintpaul infections. Initial investigations identified an epidemiologic association between illness and consumption of raw tomatoes, yet cases continued. In mid-June, we investigated two clusters of outbreak strain infections in Texas among patrons of Restaurant A and two establishments of Restaurant Chain B to determine the outbreak's source. We conducted independent case-control studies of Restaurant A and B patrons. Patients were matched to well controls by meal date. We conducted restaurant environmental investigations and traced the origin of implicated products. Forty-seven case-patients and 40 controls were enrolled in the Restaurant A study. Thirty case-patients and 31 controls were enrolled in the Restaurant Chain B study. In both studies, illness was independently associated with only one menu item, fresh salsa (Restaurant A: matched odds ratio [mOR], 37; 95% confidence interval [CI], 7.2-386; Restaurant B: mOR, 13; 95% CI 1.3-infinity). The only ingredient in common between the two salsas was raw jalapeño peppers. Cultures of jalapeño peppers collected from an importer that supplied Restaurant Chain B and serrano peppers and irrigation water from a Mexican farm that supplied that importer with jalapeño and serrano peppers grew the outbreak strain. Jalapeño peppers, contaminated before arrival at the restaurants and served in uncooked fresh salsas, were the source of these infections. Our investigations, critical in understanding the broader multistate outbreak, exemplify an effective approach to investigating large foodborne outbreaks. Additional measures are needed to reduce produce contamination.

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases ( n =152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT ( P =1.42 × 10 −12 ), 8p12 at lnc-KIF13B-1 , a long non-coding RNA (rs643472; P =3.41 × 10 −8 ), and 2p22 at SOS1 (rs963731; P =1.76 × 10 −7 ). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P =2.07 × 10 −7 ) and MAPT H1c (17q21; rs242557; P =7.91 × 10 −6 ). We previously reported SNP/transcript level associations with rs8070723/ MAPT , rs242557/ MAPT , and rs1768208/ MOBP and herein identified association with rs963731/ SOS1 . We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 ( MAPT ) and 3p12 ( MOBP ), and a novel susceptibility locus at 8p12.

Background Sex differences in progression and pathology of Alzheimer's disease (AD) suggest sex‐specific factors influencing its development. While studies have established APOE‐genotype as contributing to AD risk differently in men and women, few have searched for additional genetic sex differences in AD. To identify sex‐specific AD genetic associations, we conducted genome‐wide sex‐aware meta‐analyses in the Alzheimer's Disease Genetics Consortium (ADGC) and Alzheimer's Disease Sequencing Project (ADSP) datasets. Method Sex‐interaction and sex‐stratified analyses were performed in multi‐ancestry genome‐wide imputed AD datasets from the ADGC (N = 25,284 cases, 60% female and 33,455 controls, 63% female; ancestry/ethnicity distribution: 63.7% European, 15.6% African, 15.2% Hispanic/Latino, 5.5% Asian). STAAR aggregation‐based rare‐variant testing was also conducted in coding and non‐coding genomic regions on an ancestrally diverse sample of 8,697 AD cases and 14,758 controls with whole‐genome sequencing from the ADSP. Result Cross‐ancestry sex‐stratified analyses identified several loci with evidence of interaction (p <0.05) and suggestive significance in one sex (p <5x10‐6) and not the other (p >0.05). These include male specific variants in STXBP6, MAP4K5 and the known AD locus PICALM. Genetic loci associated in females and not males include NPAS3, ZNF438 and a genome‐wide result in NECTIN2 near the APOE locus. Top ancestry‐specific results include associations at COL4A2 in Asian‐ancestry males and C16orf96 in African‐ancestry females. Cross‐ancestry rare‐variant aggregation‐based testing revealed four novel genome‐wide significant associations in females including with missense variants in SH3BP1. Five population specific associations were also discovered including with missense variants in SERTAD4 in a genetically‐defined Hispanic/Amerindian/African ancestral population cluster and promoter variants of PSMA5 in a European population cluster. Seven male‐specific effects were also discovered including genome‐wide significant cross‐ancestry associations with an enhancer region of MORC1 and a promoter of ITPKA. Conclusion We identified sex‐specific AD associations at loci with AD‐relevant genes including STXBP6 (involved in AD relevant processes such as endolysosomal transport and synaptic transmission), NPAS3 (neurogenesis), COL4A2 (cerebral vasculature), ITPKA (learning/memory processes), PAQR3 (cholesterol homeostatis and neuronal function), and MORC1 (recently associated in a UK Biobank exome‐wide sequencing study of dementia (Zhang et al. Alz & Dementia 2024). Understanding the nature of these associations could help explain sex differences in risk and progression for AD.

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. RESULTS A novel AD‐risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, p = 3.68×10−9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10−7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. DISCUSSION These analyses identified novel AD‐associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. Highlights Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta‐analysis identified a novel genome‐wide significant AD‐risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome‐wide significance at p < 9×10−7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry‐informed genetic screening tools and therapeutic interventions.

The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is the National Institute on Aging–designated national data repository for human genetics research on Alzheimer's disease and related dementias (ADRD). NIAGADS maintains a high‐quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis, including whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project and other genotype/phenotype data, encompassing 211,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a Federal Information Security Modernization Act moderate compliant cloud‐based platform that fully supports the National Institutes of Health Genomic Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome‐wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. As a one‐stop access portal for Alzheimer's disease (AD) genetics, NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of AD. Highlights The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is a data repository for the storage of genetics and genomics data. NIAGADS houses data for Alzheimer's disease, related dementias, and healthy aging. NIAGADS offers open and qualified access data and knowledgebases to explore open access data. The Alzheimer's Disease Sequencing Project dataset is the largest Alzheimer's disease and related dementias joint called whole genome sequencing dataset (≈ 58,000 whole genomes).

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 6.8 million structural variants. Annotations and quality control data are available for all variants and samples. Additionally, detailed phenotypes from 15,927 participants across 10 domains are also provided. A linkage disequilibrium panel was created using unrelated AD cases and controls. DISCUSSION Researchers can access and analyze the genetic data via the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) Data Sharing Service, the VariXam, or NIAGADS GenomicsDB. Highlights We detailed the genetic architecture and quality of the Alzheimer's Disease Sequencing Project release 4 whole genome sequences. We identified 435 million single nucleotide polymorphisms, insertions and deletions, and structural variants from diverse genomes. We harmonized extensive phenotypes, linkage disequilibrium reference panel on subset of samples. Data is publicly available at NIAGADS Data Storage Site, variants and annotations are browsable on two different websites.

Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. To identify genetic variants associated with AD risk using a nonstatistical approach. Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative. Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Objective To identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families. Methods We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci. Results A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040). Conclusions and Relevance Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.