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

Sex modifies how APOE ε4 status relates to future dementia risk, with machine-learning discrimination reaching AUC 0.85–0.90 in APOE ε4 carriers versus 0.74–0.76 in non-carriers.

• Why it matters: It is unclear whether plasma molecular predictors of dementia differ by sex and APOE ε4 strata, limiting stratified biomarker discovery.
• What they did: In 43,759 UK Biobank participants, the study tested sex-by-APOE ε4 interactions (interaction p = 0.027) and trained proteomic/metabolomic machine-learning models to predict future dementia, then cross-checked top predictors in the Global Neurodegeneration Proteomics Consortium.
• The result: Top predictors were largely subgroup-specific (e.g., C7, CDON, EDIL3 in female carriers; KLK4, MMP12, TGFBI in male carriers), and cross-cohort ranking was retained for 12/17 female-carrier predictors and 10/16 male-carrier predictors.

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