PROJECT SUMMARY/ABSTRACT There is mounting evidence of peripheral inflammation coincident with Alzheimer’s disease (AD), yet the drivers and specific features of these immune aberrancies are unknown. Also, the connections between this peripheral inflammation and the onset and progression of dementias are not elucidated. Our previous work found that TIGIT expression on γδ T cells, a unique ‘innate-like’ T cell population, correlates with plasma markers of general inflammation in both ART-suppressed HIV infection and with normal aging and may indicate a hyper- inflammatory state of this T cell subset. γδ T cells have recently been implicated as drivers of AD pathogenesis. The Aims of my ongoing R01 award seek to define γδ T cell subset heterogeneity in our HIV and Aging cohort participants and to address our hypothesis that with aging and HIV infection, GI resident γδ T cells become aberrantly activated and cause gut leakiness, resulting in an influx of immune cells and bacterial products to the bloodstream which consequents in systemic inflammation and age-associated co-morbidities. GI abnormalities, including microbiota dysbiosis and intestinal barrier permeability, are now strongly linked to neuroinflammation, breakdown of the blood brain barrier (BBB), cognitive deficits, and AD. Therefore, as an addendum to the work proposed in my R01, we propose to expand our sample analysis to include peripheral blood and brain tissue samples from the Health Outreach Program for the Elderly (HOPE) study samples, a cohort of the NIH-funded Boston University Alzheimer’s Disease Research Center (ARDC), to build evidence in support of our hypothesis that with aging in some individuals, alterations in the GI tract induce resident γδ T cells into a hyperinflammatory state, driving gut leakiness, which results in γδ T cell influx into the circulation, systemic inflammation, and ultimately infiltration of γδ T cells and other immune components into the brain, initiating the pathogenic events that lead to AD. We propose two Aims that will examine immune cell signatures in PBMC via 32-color spectral flow cytometry, measurement of 30 markers of inflammation, neuroinflammation, and gut leakiness in plasma, and 40-marker analysis of cell signatures in brain tissue from neurotypical, mild cognitively impaired, and AD individuals. Both cross-sectional (Aim 1) and longitudinal (Aim 2) studies will be performed, with the latter enabling cause-and-effect/mechanistic insights to be gleaned via intra-individual analysis of temporally linked trajectories readout trajectories. Using bioinformatic platforms for data analysis, our proposed Aims will elucidate specific links between immune signatures and temporal trajectories with the onset and progression of neurological disease and determine connections between γδ T cells, gut leakiness, and AD. Also, our findings will provide the Preliminary Data for an AD-related R01 application and also may elucidate novel biomarkers for early ...