Country Level Incidence of Alzheimer Disease and Related Dementias is Associated with Increased Omega6 PUFA Consumption.

INTRODUCTION: Clinical and genetic studies have implicated lipid dysfunction in Alzheimer Disease (AD) pathogenesis. However, lipid consumption at the individual-level does not vary greatly within most cohorts, and multiple lipids are rarely measured in any one study. METHODS: Mean country-level lipid intakes were compared to Age-Standardized Alzheimer-Disease-Incidence-Rates(ASAIR) in 183 countries across all inhabited continents. Penalized spline regression and multivariable-adjusted linear regression, including a lag between intake and incidence, were used to assess the relationships between five lipid intakes and ASAIR. Validation was conducted using longitudinal within-country changes between 1990 and 2019. RESULTS: Omega6 Polyunsaturated-Fatty-Acid(PUFA) intake exhibited a positive linear relationship with ASAIR(multivariable-adjusted model: ß=2.44; 95%CI: 1.70, 3.19; p=1.38×10-9). ASAIR also increased with saturated-fat, trans-fat, and dietary-cholesterol up to a threshold. The association between Omega6-PUFA and ASAIR was confirmed using longitudinal intake changes. DISCUSSION: Decreasing Omega6-PUFA consumption on the country-level may have substantial benefits in reducing the country-level burden of AD.

A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer's Disease and Related Dementias (ADRD).

We developed an imputation panel for Alzheimer's disease (AD) and related dementias (ADRD) using whole-genome sequencing (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP). Recognizing the significant 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 and deletions (indels), and SVs. This panel enhances the imputation of disease susceptibility, including rare AD-associated SNVs, indels, and SVs, onto genotype array data, offering a cost-effective alternative to whole-genome sequencing while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominal significant related to AD that are absent in the TOPMed-r2 panel and identified three suggestive significant (p-value < 1E-05) AD-associated SVs in the genes EXOC3L2 and DMPK, were identified. These findings provide new insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.

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. 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.

Biobank-wide association scan identifies risk factors for late-onset Alzheimer's disease and endophenotypes.

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Furthermore, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD.

An X Chromosome Transcriptome Wide Association Study Implicates ARMCX6 in Alzheimer's Disease.

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 elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis-regulatory window were used to train tissue-specific models of each gene. We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer's Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p < 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6.

Genetic analyses in multiplex families confirms chromosome 5q35 as a risk locus for Alzheimer's Disease in individuals of African Ancestry.

There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0.01), functional potential of coding and noncoding variants, co-segregation with AD and presence in multi-ancestry ADSP release 3 WGS data. We identified a significant linkage signal on chromosome 5q35 (HLOD=3.3) driven by nine families. Haplotype segregation analysis in the family with highest LOD score identified a 3'UTR variant in INSYN2B with the most functional evidence. Four other linked AA families harbor within-family shared variants located in INSYN2B's promoter or enhancer regions. This AA family-based finding shows the importance of diversifying population-level genetic data to better understand the genetic determinants of AD on a global scale.