From Cells to Society: Using Epigenetics to Understand Brain Vulnerability to Delirium and Cognitive Decline

/ABSTRACT The goal of this proposal is to test the hypothesis that epigenetic risk and changes in epigenetic risk, measured by DNA methylation, identifies individuals with a “vulnerable brain,” who may be predisposed to unwanted outcomes, including delirium, cognitive decline, and Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) in the setting of acute stress(e.g., major surgery). Additionally, we will determine whether chronic stress (measured by social determinants of health [e.g., household income, education]) mediate these associations. Delirium and AD/ADRD have strong epidemiological associations: AD/ADRD has long-been recognized as a risk factor for delirium, and recently delirium has been implicated as a risk factor for incident AD/ADRD. Although this points to a clear link between delirium and AD/ADRD, the shared pathophysiology underlying these relationships remains largely unknown. Growing evidence highlights the role of genetics as one mechanisms linking delirium and AD/ADRD; however, not all individuals with genetic predisposition develop delirium. Therefore, other factors, possibly epigenetic, likely influence brain function and vulnerability. In the proposed R01 Specific Aims, we will address this gap in knowledge and substantially extend our prior studies by: 1) moving beyond genetics to examine the role of epigenetics, which regulate gene expression and are influenced by acute and chronic stressors, 2) developing summary measures of epigenetics specific to delirium and delirium with cognitive decline (polyepigenetic risk scores), and 3) consider the role of social determinants of health in explaining the relationships of epigenetic risk with delirium, cognitive decline, and AD/ADRD. These studies will leverage the considerable resources of three NIA-funded projects: (1 & 2) the Successful Aging after Elective Surgery Study (SAGES; P01AG031720) I and its renewal SAGES II, and (3) the Health and Retirement Study, a large cohort of older adults who already have epigenetic data available. This proposal is highly novel in examining polyepigenetic risk scores in multiple datasets with information on delirium, cognitive decline, and AD/ADRD (unavailable in most studies). Importantly, the results will inform targeted, pathophysiologically-based treatments to provide neuroprotection for vulnerable older adults, thereby potentially preventing delirium and reducing AD/ADRD, two major threats to the independence and quality of life of all older adults. Project Number: 1R01AG097804-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: SARINNAPHA VASUNILASHORN (+1 co-PI) | Institution: BETH ISRAEL DEACONESS MEDICAL CENTER, BOSTON, MA | Award Amount: $761,496 | Activity Code: R01 | Study Section: Aging Systems and Geriatrics Study Section[ASG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11275332