Developing Topics.

Background: Women are at higher risk of developing Alzheimer's disease (AD). Sex differences in AD pathobiology and prevalence appear to be partially attributed to genetics, but sex-stratified genome-wide association studies (GWAS) of AD have demonstrated a relative paucity of associated variants, which may reflect challenges of limited power. Furthermore, these studies lack information regarding the impact on sex-specific proteins and pathways relevant to AD, which limits clinical translation and targeted drug development. Sex-stratified protein quantitative trait locus (pQTL) studies pose to address these limitations. We hypothesized that directly integrating brain pQTL data with the largest to date sex-stratified AD GWAS would increase power to reveal sex-specific AD associated genes.

Method: Sex-stratified GWAS of AD from Belloy et al. 2023 included 410,276 female and 385,813 male non-Hispanic White individuals of European ancestry. Human brain proteome data with matching genome-wide data were available from Wingo et al. 2022 (N = 722) and 2023 (N = 507; N = 301). Briefly, genetic variants were associated with proteins through the FUSION package to estimate effects on protein abundance and produce non-sex-stratified (N = 2,934) and sex-stratified protein-specific variant weights (N = 1,800 for males; N = 2,463 for females). This approach retains only proteins that show significant genetic associations (i.e., protein levels displaying significant heritability). Proteome-wide association studies (PWAS) were performed via FUSION combining sex-stratified AD GWAS with non-sex-stratified and sex-stratified protein weights (Figure-1). Enrichment/pathway analysis for gene and disease ontology was conducted via the DOSE package (R 4.3.3).

Result: Sex-matched AD PWAS identified 27 and 2 AD causal genes for females and males, respectively. Sex-stratified AD GWAS integrating non-stratified protein weights identified 30 causal genes in females and 7 in males. Upon filtering results of both discoveries for sex specificity, 18 female and 2 male AD causal genes were prioritized (Figure-2). Enrichment/pathway analysis of female-specific AD causal genes highlighted metabolic-related health outcomes (Figure-3).

Conclusion: We performed sex-stratified PWAS of AD and identified 18 female-specific AD causal genes, of which 8 strikingly converged onto metabolic disorders as a putative female-specific AD pathway. These findings increase our understanding of AD pathogenesis and may inform therapeutic target development relevant to sex-specific precision medicine. Supporting analyses in additional proteogenomic resources are ongoing.