Association of Early Life Risk Factors and APOE ε4 With Incident Dementia: Evidence From 14 Years of U.S. Data

Early life is a critical period for brain development, laying the foundation for cognitive reserve. However, it remains unclear how various aspects of early life independently contribute to dementia risk, and whether these associations are modified by APOE ε4 genotype. We used data from the U.S. Health and Retirement Study (HRS), a nationally representative cohort of older adults, followed from 2006 to 2020. Our sample included 8678 community-dwelling, dementia-free participants aged ≥ 60 and < 90 at baseline with data on APOE genotype and retrospective early life conditions. Dementia incidence was classified using the validated Langa-Weir algorithm. Early life risk domains included financial capital, social capital, human capital, adversity, and health conditions. Cause-specific Cox proportional hazards models assessed the associations between these domains and incident dementia, adjusting for demographics and adulthood risk factors. To examine effect modification by genetic risk, we created 4-category group variables combining APOE ε4 status and early life risk. Deficits in financial, social, and human capital, as well as poor childhood health, were each associated with a 12%-46% increased dementia risk, independently of APOE ε4 status. After further adjusting for adulthood risk factors, low social and human capital remained significant predictors (16% and 21% increased risk, respectively). APOE ε4 was associated with an 83%-86% increased risk across all models. In effect modification analyses, early life disadvantage was associated with dementia only among non-carriers of APOE ε4, whereas ε4 carriers had elevated dementia risk regardless of early life conditions. Inadequate childhood resources may have enduring impacts on dementia risk among individuals without the APOE ε4 allele. Genetic predisposition via APOE ε4 overwhelms the influence of early life disadvantage. These findings underscore the need for dementia prevention strategies that jointly consider genetic vulnerability and early life conditions.