While risk factors for cognitive decline and Alzheimer?s Disease and related dementias (ADRD) have been widely studied, there is still much unknown about the biological pathways that lead to ADRD. This project seeks to improve our understanding of the pathophysiology of cognitive decline and ADRD by examining the role of peripheral immunosenescence in these processes. A major gap in existing research is a lack of longitudinal studies that can establish an etiologic link between peripheral immunosenescence and development of incident ADRD. In addition, there are few population-based studies examining these processes in U.S. representative samples. Population-based studies can evaluate whether clinical findings among ADRD patients are generalizable to the broader population as well as examine the role of social determinants in these processes. Despite consistently observed social inequalities in ADRD, including on the basis of race/ethnicity, sex/gender, and socioeconomic status, the pathways by which social disadvantage lead to ADRD are not well understood, limiting population-wide ADRD prevention strategies. Our long-term goal is to elucidate the role of population immunity in predicting ADRD. The overall objective of the current proposal is to evaluate the relationship between peripheral immunosenescence and domain-specific cognitive function, decline, and ADRD diagnoses in a nationally representative sample of older US adults, and, to examine the extent to which immunosenescence explains social inequalities in cognitive function, decline, and ADRD. Our central hypothesis is that immunosenescence, characterized by an increased number of senescent immune cells (e.g., CD8+CD45RA-, CD4+CD45RA-) and elevated inflammatory cytokines (C-Reactive Protein (CRP), interleukin (IL)-6, TNF-alpha) will be associated with worse cognitive outcomes, and that immunosenescence will partially explain some of the social inequalities in cognitive outcomes. The rationale for the proposed research is that immunosenescence may be an important early risk factor for ADRD, potentially representing a biological mechanism explaining population heterogeneity and inequalities in ADRD risk. To investigate these relationships, we will pursue three specific aims:1) Determine the association between peripheral immunosenescence and cognitive function and decline in the Health and Retirement Study (HRS); 2) Determine the association between peripheral immunosenescence and incident ADRD measured both by HRS cognitive assessment and linked Medicare claim data; and 3) Determine the extent to which immunosenescence explains social inequalities in cognitive function, decline, and ADRD. This proposal is innovative as it will be the first large-scale population-based study of immunity and cognition. It will yield critical insights to our understanding of the pathophysiology of cognitive decline and ADRD, and inequalities in these processes. This project is significant because the results could point to new diagnostic tools able to discern profiles of immunosenescence predictive of ADRD in the peripheral blood.
Health and Human Services, Department of-National Institutes of Health
03/01/2022 to 11/30/2026