AbstractBackgroundDetermining the effect of AD risk factors on brain aging in healthy middle‐aged and older women, compared to men, is critical for understanding whether there are sex differences in the pathways towards AD in cognitively intact, at risk adults. The goal of this study was to use an elastic net regression model to predict the effect of family history of AD [+FH] and the APOE‐e4 [+APOE4] genotype on brain age gap (BAG) in cognitively normal women and men.MethodThis cross‐sectional study used T1‐weighted structural MRIs from the Dallas Lifespan Brain Study (DLBS), South Asian Lifespan Dataset (SALD), Montreal Memory and Aging Lifespan Study (MMALS), and Pre‐symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT‐AD) cohorts. Data were collected from multiple sites: Dallas, USA (DLBS); Chonqing, China (SALD); Montreal, Canada (MMALS and PREVENT‐AD). 1067 cognitively normal adults (18‐89 years; 697 [65%] women) were randomly split into train and test sets. In the train set: 596 unknown FH (uFH) participants (mean [SD] age = 47.39 [18.46] years, 63% women); in the test set: 251 uFH (47.50 [19.15] years, 64% women) and 220 +FH participants (61.53 [6.04] years, 72% women). BAG, was measured as the difference between Predicted Age, estimated by the elastic net model, and Chronological Age.ResultThe age prediction model applied to the test set revealed greater BAG deviations in the +FH cohort compared to the uFH cohort (31% vs. 74% of the age variance, respectively; MAE = 8.22 years). A significant interaction was observed between FH status and Sex: +FH women had more advanced brain aging compared to +FH men. APOE genotype interacted with Sex in the +FH group: +APOE4 women had more positive BAG than +APOE4 men. In a sub‐cohort of individuals with AD risk factors, we observed sex differences in the role of modifiable factors of Body Mass Index and physical activity in preserving brain aging.ConclusionAD risk factors have more negative consequences to brain aging in cognitively normal women with family history than men with family history, but that modifiable factors can interact with genetic factors to potentially protect against brain aging.