Importance Nonlinear changes in brain function during aging are shaped by a complex interplay of factors, including sex, age, genetics, and modifiable health risk factors. However, the combined effects and underlying mechanisms of these factors on brain functional connectivity remain poorly understood.

Objective:

To comprehensively investigate the combined associations of sex, age, APOE genotypes, and ten common modifiable health risk factors with brain functional connectivities during aging. Design Setting and

Participants:

This analysis used data from 36,630 UK Biobank participants, aged 44-81, who were assessed for sex, age, APOE genotypes, 10 health risk factors, and brain functional connectivities through resting-state functional magnetic resonance imaging. Main Outcomes and

Measures:

Brain functional connectivities were evaluated through within- and between-network functional connectivities and connectivity strength. Associations between risk factors and brain functional connectivities, including their interaction effects, were analyzed.

Results:

Hypertension, BMI, and education were the top three influential factors. Sex-specific effects were also observed in interactions involving APOE4 gene, smoking, alcohol consumption, diabetes, BMI, and education. Notably, a negative sex-excessive alcohol interaction showed a stronger negative effect on functional connectivities in males, particularly between the dorsal attention network and the language network, while moderate alcohol consumption appeared to have protective effects. A significant negative interaction between sex and APOE4 revealed a greater reduction in functional connectivity between the cingulo-opercular network and the posterior multimodal network in male APOE4 carriers. Additional findings included a negative age-BMI interaction between the visual and dorsal attention networks, and a positive age-hypertension interaction between the frontoparietal and default mode networks. Conclusions and Relevance The findings highlight significant sex disparities in the associations between age, the APOE-ε4 gene, modifiable health risk factors, and brain functional connectivity, emphasizing the necessity of jointly considering these factors to gain a deeper understanding of the complex processes underlying brain aging.