Modifiable Risk Factors for Cognitive Decline in Community-Dwelling Older Adults Differ by Sex and APOE4

Objectives The extent to which lifestyle shapes trajectories of normal cognitive aging, and the factors with highest potential for mitigating cognitive decline, remain poorly characterized.Methods Participants of the Rancho Bernardo Study underwent demographic, health, and behavioral characterization at baseline, along with up to 7 cognitive assessments over a 27-year follow-up period. Factor analysis of 24 baseline risk variables identified 9 composite factors. Mixed effects models on data from 1,489 participants (aged 45-95 years at baseline) assessed prediction of cognitive change by baseline factor scores. Models were repeated stratified by sex and APOE4 status.Results Factors of hyperlipidemia and obesity; marriage and depression; occupation and education; and physical activity and subjective health best predicted rates of decline across multiple cognitive domains. Distinct risk profiles were identified for women and men, and for APOE4 carriers and non-carriers. Models of composite risk estimated that potential savings could amount to 7-9.5 years of preserved cognitive health span for low- versus high-risk profiles. Magnitudes of aggregate risk effects were greater among women across cognitive domains, and for APOE4 carriers for memory and verbal fluency.Discussion Multifactorial life-course approaches to manage cardiometabolic health and promote physical, cognitive, and social engagement may help to mitigate cognitive decline with age, with composite risk associated with up to a decade of preserved cognitive health span. Differences by sex and APOE4 in risk profiles and their potential for risk reduction, highlight the importance of developing personalized recommendations for multidomain approaches to cognitive health maintenance throughout the life-course.