A higher epigenetic age relative to chronological age, described as ‘epigenetic age acceleration (EAA),’ indicates that an individual is biologically older than their years. The investigative team recently showed that EAA is associated with lower cognitive function (e.g., episodic memory, phonemic fluency) and lower white matter and total brain volumes, supporting a role of EAA in cognitive and brain health. Yet, while age is the strongest risk factor for Alzheimer’s disease and related dementias (ADRD), the association of EAA with mild cognitive impairment (MCI), ADRD, and brain aging is vastly understudied. The NIA’s 2020-2025 Strategic Directions for Research goals include understanding how “molecular bases of changes associated with aging contribute to the development and course of age-related dementia” and identifying “biological and clinical markers for early detection of cognitive decline, MCI, and AD.” Towards these goals, the overall objective of this project is to clarify the association of EAA with MCI, ADRD, successful cognitive aging, and brain aging in a nested case-cohort (N=2,836) within the deeply phenotyped, racially and ethnically diverse, NIA-funded Women’s Health Initiative Memory Study (WHIMS). With 25 years of follow-up that will continue at least through 2021, WHIMS contains detailed data on longitudinal measures of cognitive function; 1,336 incident cases of rigorously ascertained MCI and ADRD; genome-wide genotyping; and longitudinal neuroimaging measures of brain health. As an innovative aspect of this study, novel genome-wide DNA methylation data using stored blood DNA from two study visits 14- 18 years apart will be generated to examine changes in EAA. The Aims are to: 1) determine the extent to which EAA is associated with higher risk of MCI and ADRD and lower likelihood of survival to age 90 without cognitive impairment; 2) determine the extent to which EAA is associated with decreased total and regional brain volumes and increased total ventricular and white matter lesion volumes; and 3) identify epigenetic signatures across the genome associated with these cognitive and brain outcomes in epigenome-wide association studies (EWAS). Moderation of associations by race/ethnicity, APOE ε4 carriage, polygenic risk for AD, and cardiovascular disease will be explored. Findings will be replicated and extended in well-phenotyped, independent cohorts of men and women with data on genome-wide DNA methylation and cognitive and brain outcomes. Given that the pathophysiological ADRD process can begin up to 20 years before symptom onset, understanding the role of EAA as an aging biomarker identifying older adults early in the disease course is imperative to potentially prevent irreversible cognitive and functional decline. This study also presents a unique opportunity to identify age- associated epigenetic mechanisms of MCI, ADRD, and accelerated brain aging with potential to act as therapeutic targets to promote preserved cogniti...