biostudies-literatureUnknownCook NBLRD VANIA NIH HHSSex 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 <i>Epidermal Growth Factor Receptor</i> (<i>EGFR</i>), were uniquely prioritized in women. Finally, we identified <i>Haptoglobin</i> (<i>HP</i>) 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.medRxiv : the preprint server for health sciences2025.10.31.25339089https://www.ebi.ac.uk/biostudies/studies/S-EPMC12636628biostudies-literatureIntegrative Genetic, Proteogenomic, and Multi-omics Analyses Reveal Sex-Biased Causal Genes and Drug Targets in Alzheimer's Disease.PMC12636628IK4 BX005219R01 AG089509R01 AG071706I01 BX005686R01 AG072120R01 AG075827R00 AG075238R01 AG064614R01 AG078964R01 AG074007R00 AG071837R01 AG058501Le Guen YAltmann AYoung CNapolioni VWingo APTalozzi LZeng YYang CWestern DFinnGenMormino ECCruchaga CBelloy MELiu YCook NStewart IWingo TSHe ZSong SGreicius MDSivasankaran SKSung YJfalseIntegrative 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 <i>Epidermal Growth Factor Receptor</i> (<i>EGFR</i>), were uniquely prioritized in women. Finally, we identified <i>Haptoglobin</i> (<i>HP</i>) 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.2025-01-01T00:00:00Z2025 Nov2026-06-10T03:14:06.965Z2026-06-10T03:07:55.254ZS-EPMC126366284128279310.1101/2025.10.31.25339089