Epigenetic Age Acceleration as a Biomarker of Early Life Adversity and Mid-life Cognitive Function

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ABSTRACT Early life adversity affects two-thirds of all children in the U.S. and can have a lasting impact on healthy cognitive aging, interfering with the acquisition of cognitive abilities in early life and leading to earlier, steeper declines in cognitive function at mid-life. Theoretical models specify that early life adversity alters biological stress-mediating systems underlying broad domains of cognitive health. The biological effects of early life adversity can therefore serve as highly novel biomarkers with the unique advantage of being detected prior to cognitive impairment. Identifying biomarkers at mid-life, prior to the onset of cognitive impairment or even neurodegenerative diseases such as Alzheimer's Disease and related dementias, can provide actionable information to improve early detection and efforts at delaying, reversing, or preventing these conditions in late- life. This proposal will examine whether early life adversity alters a novel biomarker of cognitive function at mid- life, epigenetic age, an index of the biological age of human tissues and cells derived from DNA methylation and predictive of cognitive impairment in late-life. Existing data and biospecimens will be used to examine the impact of early life adversity on epigenetic age and its relation to cognitive function at mid-life in the Female Growth and Development Study (N=173; Mage=39.47), a 30-year prospective cohort study of the impact of child sexual abuse. Active data collection with the Female Growth and Development Study is underway and examining the impact of child sexual abuse on cognitive function using well-established, performance-based measures of working memory, inhibitory control, fluid reasoning, and receptive language. The current application would capitalize on this opportunity by advancing comprehensive biological models for how child sexual abuse is embedded in the methylome to affect cognitive function at mid-life. DNA and genome-wide variation in DNA methylation will be characterized through whole blood. DNA methylation at 353 cytosine- guanine sites across the methylome will be used to quantify epigenetic age and examine its relation with child sexual abuse. Mediation models will test whether glucocorticoid remodeling occurring in the sixteen years following child sexual abuse explains accelerations in epigenetic age at mid-life. Variably methylated regions of the methylome affected by child sexual abuse will also be examined to identify regions that have the strongest risk and protective relations with cognitive function at mid-life. Epigenetic age and other established risks, including a cognitive function polygenic risk score, educational attainment, socioeconomic status, and lifetime exposure to stressful events, will be included in statistical models to examine the increased predictive power gained from these molecular analyses of cognitive function beyond known risks. Following recommendations by the National Institute on Aging, this proposal will test epigenetic age as a unique biomarker of cognitive function at mid-life following early life adversity to identify those at greatest risk for cognitive impairment and decline in late-life.