Abstract In the United States, 1 in 9 individuals 65 and older and one third of individuals 85 and older have Alzheimer’s dementia (AD). By age 70, age-related cognitive decline is nearly ubiquitous with signs of mild cognitive impairment in a large portion of older adults. Exercise is a promising intervention to mitigate cognitive decline in older adults, however response to exercise varies. Epigenetic age, particularly accelerated epigenetic aging, has been linked to neurodegenerative disorders including AD, other types of dementia and cognitive aging. Understanding the impact of social determinants of health (SDoH) on epigenetic aging is gaining momentum with several studies implicating cumulative lifetime stress, lifestyle, early life adversity, and neighborhood context with epigenetic age acceleration. The impact of exercise on DNA methylation is well established and its impact on epigenetic aging is a burgeoning area of research. Elucidating biologic underpinnings related to variability in cognitive function (CF), brain health (BH), biomarkers of AD, and response to exercise are necessary to improve mitigation of age-related cognitive decline. The overarching hypothesis for this project is that heterogeneity of biological aging explains variation in CF, BH, biomarkers of AD, and response to exercise in non-cognitively impaired older adults. This project will be accomplished by harnessing the data and biospecimens collected through the Investigating Gains in Neurocognition in an Intervention Trial of exercise (IGNITE) project. Participants (n=648) were 65-80 years old, community dwelling, not cognitively impaired individuals who exercised <20 minutes/week. Participants were randomized to a 12 month intervention to 1 of 3 groups: group 1=150 minutes/week moderate intensity aerobic exercise; group 2=225 minutes/week moderate intensity aerobic exercise; group 3=light intensity stretching 150 minutes/week (control). An extensive cognitive function battery and blood were collected at baseline (month 0), midpoint (month 6) and completion (month 12) of intervention, neuroimaging at 0 and 12 months, amyloid β at month 0 and AD biomarkers at month 0 and 12. Data on lifestyle and social determinants of health were also collected. The aims of this study are to determine the effect of epigenetic age acceleration on CF, BH, and biomarkers of AD in older adults; determine the effect of a dose response moderate intensity exercise intervention on epigenetic age acceleration in older adults; examine the role of epigenetic age acceleration CF, BH, and biomarkers of AD in older adults within the context of a 12-month dose-response exercise intervention; and examine the effects of SDoH and their interaction with epigenetic age acceleration on CF, BH, and biomarkers of AD in older adults within the context of a 12-month dose-response exercise intervention.

Alzheimer’s dementia (AD) and age-related cognitive decline have a large impact on the health of Americans. Age is the primary risk factor for AD and cognitive decline. Aging can be chronologic aging (time since birth) or biological aging that may differ substantially from chronological age for some individuals. Exercise is a promising intervention to mitigate cognitive decline in older adults. Understanding the impact of exercise on biological aging and cognitive function could assist in improving interventions to impede the development of AD and age-related cognitive decline.