Sex-aware Cross-tissue Regulatory Transformer Identified Sexually Dimorphic Alzheimer's Disease Risk Loci and Causal Cellular Circuit

Sex differences in Alzheimer's disease (AD) genetic effects and regulatory contexts remain incompletely resolved. We analyzed 449,335 European-ancestry participants using sex-stratified and genotype-by-sex models and developed STAGE-AD, a Transformer integrating molecular QTLs, epigenomic and single-cell annotations. Sex-stratified analyses identified eight female and three male genome-wide-significant signals provisionally classified as novel. Primary test-set area under the precision-recall curve was 0.895 (95% confidence interval, 0.877-0.912), decreasing to 0.751 under locus hold-out and 0.681 under APOE-region hold-out. Statistical-genetic integration in independent HUNT and MVP cohorts supported 236 genes at 106 loci. Prespecified lifetime-risk assumptions yielded liability-scale SNP heritabilities of 11.42% in females and 9.23% in males. Ablations indicated that female-biased predictions depended on glial annotations and male-biased predictions on endothelial and oligodendrocyte annotations. Eleven candidate variant-gene-tissue-cell-pathology chains were evaluated using multi-omics and neuropathological data from 579 NPAD brain donors. These findings underscore the importance of considering sex-specific genetic architectures in the study of health conditions, including Alzheimer's disease, paving the way for more targeted treatment strategies.