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

Abstract

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.

Plain Language Summary

There are many risk factors for dementia. We wanted to know if there are unique patterns of risk between females and males. In other words, are there sex differences in the risk factors for dementia?

To begin to answer this question, we used data from three large Canadian studies on aging and dementia. We studied the patterns of risk separately for males and females.

Our findings demonstrated that the networks of risk factors were different for females and males. For example, vascular health factors played a stronger role in females’ risk factors. But mental health factors were more central in males’ risk factor patterns.

These findings matter because they can help us to have more accurate risk reduction strategies.   Dementia risk is not the same for everyone. Sex-specific health strategies—such as better heart health monitoring in females, or mental health support for males—could help delay or prevent cognitive decline.