The goal of this proposal is to test the hypothesis that neuroinflammation is a shared pathophysiological pathway linking delirium and Alzheimer's disease and related dementias (ADRD), and that these relationships differ by genetic predisposition. Delirium and ADRD have strong epidemiological associations: ADRD has long- been recognized as a risk factor for delirium, and recently delirium has been implicated as a risk factor for incident ADRD. Although this points to a clear link between delirium and ADRD, the shared pathophysiology underlying these relationships remains largely unknown. In the proposed R03 Specific Aims, we will address this gap in knowledge and substantially extend our preliminary studies that have focused only on plasma- based markers of inflammation by examining whether both plasma and cerebrospinal fluid (CSF)-based measures of neuroinflammation are associated with postoperative delirium and incident ADRD, and evaluate whether genetic risk modifies these associations. These studies will leverage the considerable resources of: 1) the NIA-funded program project, the Successful Aging after Elective Surgery Study (SAGES; P01AG031720), and 2) the Healthier Postoperative Recovery Study (HiPOR; R21AG048600). This proposal is highly novel in examining markers of neuroinflammation and neuronal injury that will advance our understanding of the pathophysiologic mechanisms underlying the delirium-ADRD relationship, a largely underexplored area that represents a top priority area of the NIH (PAR-17-038). Importantly, the results will inform pathophysiologically targeted treatment for inflammation to provide neuroprotection and identify important variables to refine delirium risk prediction strategies thereby potentially preventing delirium and reducing ADRD, two major threats to the independence and quality of life of all older adults.
Delirium (acute confusional state) is a common, morbid, and costly geriatric syndrome, with strong epidemiological associations with Alzheimer's Disease and Related Dementias (ADRD): ADRD is a well- established risk factor for delirium, and delirium is increasingly recognized as an independent risk factor for incident ADRD. This clinical and translational project examines older patients undergoing major elective surgery to advance our understanding of the potential shared pathophysiology underlying the delirium-ADRD relationship. Our findings will inform targeted strategies to provide neuroprotection in this important population, thereby potentially preventing delirium and reducing ADRD.