The Interaction Effects of Age, Sex, APOE and Common Health Risk Factors on Human Brain Functions

Recent studies have shed light on the complex nonlinear changes in brain functions across the lifespan, demonstrating the variability in the individual cognitive and neural development during aging. This variability is influenced by factors such as sex, age, genetics, and modifiable health risk factors (MHRFs), which collectively shape unique patterns of brain functional connectivities (FCs) across different regions. However, their joint effects and underlying mechanisms remain unclear. We conduct a comprehensive analysis to jointly examine the association of common risk factors with brain functional measures, using data from 36,630 UK Biobank participants aged 44-81. Participants were assessed for age, sex, Apolipoprotein E (APOE) genotypes, ten common MHRFs, and brain FCs measured via resting-state functional magnetic resonance imaging. Using the fine-grained HCP-MMP parcellation and Ji-12 network atlases, we identified 91 associations with network functional connectivity (NFC) and 102 associations with network edge strength (NES) measures. Hypertension, BMI, and education emerged as the top three influential factors across networks. Notably, a negative interaction between sex and APOE4 genotype was observed, with male APOE4 carriers showing greater reductions in NFC between the cingulo-opercular (CON) and posterior multimodal (PMN) networks. Additionally, a negative age-BMI interaction on NES between the visual and dorsal attention (DAN) networks suggested that higher BMI accelerates the decline in visual-DAN connectivity. A positive age-hypertension interaction between the frontoparietal (FPN) and default mode (DMN) networks indicated a more rapid decrease in functional segregation associated with hypertension. We also identified sex-education interactions, showing more pronounced positive effects on CON-FPN networks in females and PMN-DMN networks in males. Further interactions involving sex and other MHRFs, such as smoking, alcohol consumption, diabetes, and BMI, revealed that smoking, alcohol, and BMI had more detrimental effects in males, while diabetes had a more pronounced negative impact in females within specific networks. These findings underscore the necessity of jointly considering sex, age, genetic factors, and MHRFs to accurately delineate the multifactorial alterations in the FCs during brain aging.