Brain Vulnerability in Delirium and Alzheimer’s Disease and Related Dementias: Intersection of Polygenic Risk and Inflammation

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PROJECT SUMMARY/ABSTRACT The goal of this proposal is to test the hypothesis that genetic risk for Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) identifies individuals with a “vulnerable brain,” who may be predisposed to bad outcomes, including delirium, cognitive decline, and AD/ADRD, in the presence of an inflammatory insult (e.g., surgery or infection). 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 inflammation as a common biological mechanism of delirium and AD/ADRD, but not all individuals with high inflammation develop delirium and/or AD/ADRD. Therefore other predisposing factors (possibly genetic) likely influence the effect of inflammation on the brain. In the proposed R01 Specific Aims, we will address this gap in knowledge and substantially extend our prior studies by: 1) moving beyond single candidate gene approaches to examine the synergistic effects of multiple genetic loci (e.g., polygenic risk scores, shown to enhance clinical prediction of AD/ADRD), and 2) consider how polygenic risk of AD/ADRD and inflammation interact to increase risk of delirium, cognitive decline, and AD/ADRD. These studies will leverage the considerable resources of six datasets: (1 & 2) the NIA-funded program project, the Successful Aging after Elective Surgery Study (SAGES; P01AG031720) I and its renewal SAGES II, (3) INTUIT [Investigating NeuroinflammaTion UnderlyIng Postoperative Brain Connectivity Changes, Postoperative CogniTive Dysfunction, Delirium in Older Adults; K76-AG057022 and UH2/3 AG056925], (4) MADCO-PC [Markers of Alzheimer’s Disease and Cognitive Outcomes after Perioperative Care], (5) MARBLE [Modulating ApoE signaling to Reduce Brain inflammation, deLirium, and postopErative cognitive dysfunction; R03AG050918]; and 6) the population-based UK Biobank, a large cohort of older adults who have already been genotyped. This proposal is highly novel in examining polygenic risk scores and their relationship with inflammation in multiple datasets with information on delirium 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.