Mid-to-Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals
Authors: Xu Yuexuan , Sun Zhongxuan , Jonaitis Erin , Deming Yuetiva , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D. 
Published: May 2024

ABSTRACTIMPORTANCEGenetic and lifestyle factors contribute to an individual’s risk of developing Alzheimer’s disease. However, it is unknown whether and how adherence to healthy lifestyles can mitigate the genetic risk of Alzheimer’s.OBJECTIVEThe aim of this study is to investigate whether adherence to healthy lifestyles can modify the impact of genetic predisposition to Alzheimer’s disease on later-life cognitive decline.DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort study included 891 adults of European ancestry, aged 40 to 65, who were without dementia and had complete healthy-lifestyle and cognition data during the follow-up. Participants joined the Wisconsin Registry for Alzheimer’s Prevention (WRAP) beginning in 2001. We conducted replication analyses using a subsample with similar baseline age range from the Health and Retirement Study (HRS).EXPOSURESWe assessed participants’ exposures using a continuous non-APOEpolygenic risk score for Alzheimer’s, a binary indicator forAPOE-ε4carrier status, and a weighted healthy-lifestyle score, including factors such as no current smoking, regular physical activity, healthy diet, light to moderate alcohol consumption, and frequent cognitive activities.MAIN OUTCOMES AND MEASURESWe z-standardized cognitive scores for global (Preclinical Alzheimer’s Cognitive Composite score 3 – PACC3) and domain-specific assessments (delayed recall and immediate learning).RESULTSWe followed 891 individuals for up to 10 years (mean [SD] baseline age, 58 [6] years, 31% male, 38%APOE-ε4carriers). After false discovery rate (FDR) correction, we found statistically significant PRS × lifestyle × age interactions on preclinical cognitive decline but the evidence is stronger amongAPOE-ε4carriers. AmongAPOE-ε4carriers, PRS-related differences in overall and memory-related domains between people scoring 0-1 and 4-5 regarding healthy lifestyles became evident around age 67 after FDR correction. These findings were robust across several sensitivity analyses and were replicated in the population-based HRS.CONCLUSIONA favorable lifestyle can mitigate the genetic risk associated with current known non-APOEgenetic variants for longitudinal cognitive decline, and these protective effects are particularly pronounced amongAPOE-ε4carriers.KEY POINTSQuestion:Can a healthy lifestyle modify genetic susceptibility to Alzheimer’s disease and its impact on cognitive decline?Findings:In two longitudinal studies, we found that adhering to a healthy lifestyle can reduce the adverse genetic effects of known non-APOEvariants, especially inAPOE-ε4carriers. Specifically,APOE-ε4carriers with <2 healthy lifestyle factors had significantly higher genetic risk caused by currently known genetic variants compared to those with two or more.Meaning:A healthy lifestyle can mitigate genetic risks from non-APOEvariants, especially amongAPOE-ε4carriers. Future research should include biomarker analysis to uncover the underlying biological mechanisms.