Sex-Specific Effects of APOE4 on Multimodal Biomarkers Across the Alzheimer's Disease Spectrum: A Comprehensive Interaction Analysis

Background: The APOE4 allele represents the strongest genetic risk factor for Alzheimer's disease, though emerging evidence suggests its effects may be sex-dependent. This study comprehensively investigated sex-specific APOE4 effects across multimodal biomarkers in a well-characterized cohort spanning the AD continuum. Methods: We analyzed 684 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) including cognitively normal (n=159), mild cognitive impairment (MCI, n=443), and Alzheimer's disease (AD, n=82) individuals. Sixteen clinical variables encompassing neuroimaging, cerebrospinal fluid biomarkers, metabolic profiles, and cardiovascular measures were examined. Results: our analysis revealed significant sex-by-APOE4 interactions for the majority of biomarkers. Large effect sizes were found for total white matter (ε²=0.242), HDL cholesterol (ε²=0.186), total gray matter (η²=0.375), and total CSF volume (η²=0.222). The MCI stage showed the most pronounced interactions, with significant effects on FDG-PET metabolism (ε²=0.040), phosphorylated tau (ε²=0.123), and lipid profiles. Phosphorylated tau demonstrated substantial sex-specific genetic effects across all diagnostic groups. Conclusions: Our findings reveal widespread, robust sex-dependent APOE4 effects, particularly during the MCI stage. These results emphasize the crucial importance of considering sex as an effect modifier in AD genetic risk and highlight potential targets for sex-specific therapeutic interventions.