Accelerated Epigenetic Aging as a Mechanism in Lifespan Socioeconomic Effects on Midlife Cognitive Decline

Project Summary/Abstract Progressive cognitive decline including Alzheimer’s Disease and its related dementias (ADRD) does not suddenly occur in later life; it emerges over time, influenced by many mechanisms across the lifespan. Evidence links individual- and, more recently, community-level socioeconomic conditions to cognition later in life, yet what remains unknown is the timing and mechanism by which these socioeconomic factors affect cognitive function and decline. In terms of the timing: We propose to test the impact of timing of exposure to socioeconomic disadvantage for cognitive health in midlife using four lifespan models: 1) Sensitive Period model– focuses on childhood exposure to disadvantage; 2) Cumulative model– focuses on accumulated exposure across the lifespan to disadvantage; 3) Pathways model– proposes that childhood disadvantage predicts health via adulthood disadvantage; and 4) Social Mobility model– proposes that childhood and adulthood disadvantages interact to affect health. In terms of the mechanism: We propose to longitudinally examine accelerated epigenetic aging as a biological mechanism connecting lifespan individual and community socioeconomic disadvantage to poorer cognitive function and greater decline in midlife. This link has not been tested but it builds on recent evidence, including our own, that older epigenetic age (higher DNA methylation-based biological age relative to chronological age) is associated with cognitive decline and dementia. Our primary aims, then, incorporate lifespan models to test when individual and community socioeconomic disadvantage independently predict Time 1 (T1) levels and T1-to-T2 changes 10-16 years later across midlife in epigenetic aging and cognitive function, and whether associations between socioeconomic disadvantage and cognitive function and decline are explained by accelerated epigenetic aging. We will leverage the deeply phenotyped longitudinal Adult Health and Behavior project with existing data on individual socioeconomic disadvantage in childhood and adulthood, neuropsychologically-assessed cognitive function, and stored blood at both T1 (30-54 yrs old, N=1773) and T2 (N=706) 10-16 years later. We will re-recruit the T2 sample to obtain new data on lifespan community socioeconomic disadvantage. We will use the stored blood to calculate epigenetic age at T1 and T2 in the entire sample. This project is innovative in several ways: longitudinal assessment of a molecular aging mechanism linking socioeconomic factors to cognitive health; the lifespan perspective providing basic scientific insights to enhance the timing and effect of prevention/interventions by targeting socioeconomic disparities at certain life stages; and the focus on midlife as an especially critical developmental window to observe epigenetic and cognitive changes and identify who may be on a trajectory of risk for ADRD. We anticipate study results will contribute new knowledge to determine when and how socioeconomic factors as stress exposures may accelerate epigenetic aging and lead to declines in cognition.