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.
