Age is the largest risk factor for dementia and cognitive decline. Many people living with HIV (PLWH) are aging and at risk for Alzheimer Disease and Related Dementias (ADRD). Physical inactivity is a well-established modifiable risk factor for dementia and increased physical activity (PA) is associated with improvements in some markers of inflammation. Novel plasma biomarkers of ADRD (amyloid-beta (Aβ), phosphorylated tau (pTau), and neurofilament light (NfL)) have been identified and are elevated in people living without HIV in association with ADRD. Elevations of NfL in the cerebrospinal fluid (CSF) can be seen with HIV-associated neuroinflammation, levels of Aβ and pTau may be less sensitive to inflammation. Plasma concentrations of Aβ, pTau, and NfL in PLWH are not well-defined. It is unknown to what extent global cognitive function, physical performance, frailty, PA, and inflammatory markers are associated with plasma biomarkers of ADRD among older PLWH. We are leveraging the parent study Optimization of a behavioral intervention to increase physical activity in older adults living with HIV (R01AG077989) for this administrative supplement (responding to NOT- AG-23-015) focused on plasma biomarkers of inflammation and ADRD. Two-hundred PLWH aged 50 years and older with low baseline physical activity and without dementia will be recruited for the parent study with assessment of cognitive function using the Montreal Cognitive Assessment (MoCA, anticipate a range of scores in the normal and mild-to-moderate impairment range) at baseline, assessments of physical performance (Short Physical Performance Battery, SPPB) and the frailty phenotype (modified Fried criteria) at baseline and month 4, and ongoing detailed characterization of PA (steps/day). Our objective for this supplement proposal is to characterize biomarkers indicative of risk for ADRD, and factors that influence levels of these biomarkers, among a cohort of PLWH with low baseline PA. We will first examine cross-sectional associations between plasma NfL (primary predictor), Aβ42/Aβ40, and pTau and global cognitive function (primary outcome), physical performance, frailty, and biomarkers of systemic inflammation (hsCRP, IL-6, sCD163, sCD14, D-dimer). We will then determine if level of PA at baseline, and changes in PA over time, are associated with baseline levels, and changes in levels, of plasma biomarkers of ADRD and inflammation. We hypothesize that levels of PA and inflammatory markers will be associated with NfL, but not Aβ42/Aβ40 and pTau, consistent with NfL more closely reflecting neuroinflammation. This study will provide novel data related to associations of plasma Aβ, p-tau, and NfL levels with inflammatory risk markers that have been well- validated in this population. We will also identify potential associations with key lifestyle and behavioral factors that may affect levels of plasma ADRD biomarkers in PLWH. Findings will inform research using larger cohorts to develop ...