Integrative Genetic, Proteogenomic, and Multi-omics Analyses Reveal Sex-Biased Causal Genes and Drug Targets in Alzheimer’s Disease

Sex differences are pervasive in Alzheimer’s disease, but the underlying drivers remain poorly understood. To address this, we performed sex-stratified genome-wide association studies of Alzheimer’s disease in ∼1,000,000 individuals, which we subsequently integrated with proteogenomics datasets from neurological tissues to identify candidate causal genes. We further prioritized genes through additional multi-omics approaches, including quantitative trait locus summary-based mendelian randomization and colocalization. Altogether, we prioritized 125 female-biased and 21 male-biased risk genes. Female-biased pathways included amyloid, neurite, stress, clearance, and immune processes, with genes enriched for microglia and astrocyte expression. Through computational drug repurposing analyses, a set of sex hormone related drugs, converging on Epidermal Growth Factor Receptor ( EGFR ), were uniquely prioritized in women. Finally, we identified Haptoglobin ( HP ) as a female-specific gene, leveraging long-read sequencing approaches to implicate a link to oxidative stress, APOE, and hemoglobin biology. Altogether, our findings provide a portal into sex-specific precision medicine for Alzheimer’s disease.