Book Description

The etiology of Alzheimer's disease is multifaceted, involving a complex interplay of environmental and genetic factors. APOE [epislon]4 has been identified as the strongest genetic risk factor for Alzheimer's. Recent genome-wide association studies have also identified many non-APOE genetic variants that significantly contribute to Alzheimer's risk. Since these non-APOE variants typically have small effects, researchers often prefer to use a polygenic risk score to create a more robust predictor by combining the effects of these variants. However, the roles of APOE and non-APOE polygenic risk score in the disease's etiology, particularly during the preclinical stage of Alzheimer's, and whether different environmental exposures throughout life can modify the predisposed risk from APOE and non-APOE polygenic risk score, remain largely unknown. In this study, leveraging two longitudinal studies, we comprehensively evaluate how APOE, non-APOE polygenic risk score, and various environmental factors throughout life individually and jointly affect an individual's risk of Alzheimer's. We found that the effect of non-APOE polygenic risk score is particularly strong among APOE [epislon]4 carriers. Additionally, we observed that maintaining healthier lifestyles in mid-to-late life, or having an advantaged childhood socioeconomic status, can mitigate the adverse genetic effects of non-APOE polygenic risk score on later-life cognitive decline, especially among APOE [epislon]4 carriers. The findings from this research can serve as a foundation for future clinical trials and provide evidence for policymakers in designing effective policy interventions to address health disparities in Alzheimer's.