Exploring sex-specific risk factors in cognitive decline: Insights into modifiable and non-modifiable determinants using a network analysis.

BACKGROUND: How sex-specific risk factors for dementia interact remains understudied. Network analysis provides a novel approach to examine these relationships, offering insights into sex-specific risk factor connectivity in healthy controls (HCs) and individuals with mild cognitive impairment or Alzheimer's disease (cognitive decline [CD]). METHODS: A network analysis of 896 participants examined associations among modifiable, non-modifiable, and cognitive risk factors. Network invariance and global strength tests assessed structural and connectivity differences. RESULTS: In males, network invariance differed between HC and CD groups, but connectivity was unchanged. In females, network invariance and connectivity were significantly altered, with HC females exhibiting stronger overall connectivity. Key risk factors in females included systolic blood pressure and apolipoprotein E ε4, whereas males' networks were primarily influenced by cognitive outcomes. DISCUSSION: Sex-specific networks suggest distinct mechanisms underlying cognitive decline. Future work differentiating mild cognitive impairment and Alzheimer's disease stages will refine our understanding of risk factor evolution and inform precision medicine approaches to dementia prevention. HIGHLIGHTS: Sex-stratified networks of risk factors differ in healthy and cognitively impaired adults. Female networks show greater global connectivity in healthy versus cognitively decline groups. Apolipoprotein E, family history, and lifestyle factors show sex-specific centrality in networks. Network structure changes more in females across the cognitive decline spectrum. Findings support sex-specific modeling of dementia risk for precision prevention.