Association of Early Life Risk Factors and APOE ε4 with Incident Dementia: Evidence from 14 Years of Data from the U.S. Health and Retirement Study

BackgroundEarly life is a critical period for brain development, laying the foundation for cognitive reserve. However, it remains unclear how various aspects of early life relate to dementia risk, and how they may interact with genetic predisposition. MethodsThis study leverages data on nationally representative older adults in the United States from the Health and Retirement Study (2006-2020; N=8,676; ages [≥] 60 at baseline, 55% female). We used Cox proportional hazards models to evaluate the associations of early life risk factors (financial, social, human capital deficits, adverse experiences, and childhood health conditions) and their interactions with APOE {varepsilon}4 genotype on dementia incidence. ResultsLow early-life financial, social, and human capital, as well as childhood health conditions were associated with higher dementia risk. After adjusting for comprehensive adulthood risk factors, low social capital and human capital persisted as significant predictors, associated with 16% (95% CI=1-34%) and 21% (95% CI=6-38%) increased risks, respectively. APOE {varepsilon}4 strongly predicted dementia across all models (83-86% increased risk). Notably, significant interactions emerged between APOE {varepsilon}4 and early-life financial capital and adversity. These early life risk factors significantly increased dementia risk only among APOE {varepsilon}4 non-carriers. Carrying {varepsilon}4, however, consistently elevated risk regardless of childhood socioeconomic status or adversity exposure. ConclusionsOur findings suggest potential direct, enduring cognitive health impacts of inadequate childhood social and human resources, and show that genetic predisposition via APOE {varepsilon}4 may overwhelm the influence of early life socioeconomic adversity, providing evidence consistent with a differential susceptibility hypothesis.