Sex shapes plasma molecular signatures of dementia risk across APOE ε4 strata

Sex and APOE ε4 influence dementia risk, but whether its molecular predictors differ across sex and APOE ε4 strata remains unclear. We investigated plasma proteomic and metabolomic signatures predicting future dementia in 43,759 UK Biobank participants across four sex-by-APOE ε4 groups. The association between APOE ε4 carrier status and dementia differed by sex (interaction p = 0.027). Machine-learning models achieved higher discrimination in APOE ε4 carriers (AUC 0.85-0.90) than non-carriers (AUC 0.74-0.76), with the highest performance in female carriers. Most top molecular predictors were subgroup-specific, including C7, CDON and EDIL3 in female carriers and KLK4, MMP12 and TGFBI in male carriers. When UK Biobank models were applied to the Global Neurodegeneration Proteomics Consortium, 12/17 available top predictors in female carriers and 10/16 in male carriers remained highly ranked. These findings identify distinct molecular signatures of dementia risk across sex and APOE ε4 strata, supporting stratified biomarker discovery.