Mid‐to‐Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals from the Wisconsin Registry for Alzheimer’s Prevention

Background Genetic and lifestyle factors contribute to an individual’s risk for developing Alzheimer’s disease (AD). A better understanding of interactions between these factors may help design targeted interventions. In this study, we investigated whether number of long‐term healthy lifestyles modified the effect of genetic predisposition to AD on cognitive decline during the preclinical stage of AD. Methods We evaluated longitudinal associations of cognitive aging with a healthy lifestyle composite score, which included physical activity, diet, smoking, cognitive activity, and alcohol consumption, and the interaction of the healthy lifestyle composite score with APOE ε4 carrier status and a non‐ APOE polygenic risk score (PRS) in a sample of 848 individuals from the Wisconsin Registry for Alzheimer’s Prevention (Table 1). The primary outcome was a multi‐domain cognitive composite (PACC3); secondary outcomes were immediate/delayed memory and executive function composites. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation. Results Favorable lifestyles can marginally modify the age dependent influence of APOE on PACC3 ( p = 0.1) and executive function ( p = 0.14), and significantly mitigate the adverse effect of APOE ε4 on delayed recall as people aging ( p < 0.01, Figure 1). However, we observed no statistically significant interactions between non‐ APOE PRS, combined lifestyle factors, and age for all the assessed cognitive outcomes (Figure 2). When we further stratify the sample by the APOE ε4 carrier status, we found the interaction between non‐ APOE PRS, age, and healthy lifestyle is statistically significant for PACC3 ( p = 0.02) and delayed recall ( p < 0.01) and marginally significant for immediate learning ( p = 0.06) among APOE ε4 carriers (Figure 3). Among APOE ε4 noncarriers, combined lifestyle factors can only modify the age‐dependent adverse genetic influence of non‐ APOE PRS on PACC3 ( p = 0.01), but the protective effect is more evident at a younger age (Figure 4). These results are robust to multiple sensitivity analyses. Conclusion A favorable lifestyle can mitigate the genetic risk caused by both APOE ε4 and non‐ APOE PRS, but the protective effect against non‐ APOE PRS is more evident among APOE ε4 carriers.