PROJECT SUMMARY Older people with HIV (PWH) in the United States are a rapidly expanding group and are at increased risk for cognitive impairment despite virologic suppression. While declining cognitive function is a critical contributor to reduced quality of life and currently affects 20-50% of PWH, there are no effective diagnostics or therapeutics to predict and track disease progression and to mitigate morbidity in PWH with cognitive impairment on antiretroviral therapy. As more providers in HIV and primary care clinics care for an aging population with HIV, we recognize the need for minimally-invasive diagnostics such as blood-based biomarkers to assess cognitive function. Blood-based biomarkers that can detect proteins produced by neurons or glial cells are poised to become clinically available as part of a repertoire of diagnostic tools in memory clinics. Assessing the diagnostic performance of these blood biomarkers in predicting cognitive impairment and its progression in large cohorts of older PWH on antiretroviral therapy is critically important. In the parent R01 (R01AG069575), the PI (Dr. Emily Hyle) and research team detailed methods for developing and populating a simulation model of dementia and multimorbidity for the aging HIV population, the CHARMED (Cognitive impairment, HIV, Aging, heaRt, MEntal health, and Dementia) model. In this administrative supplement, the research team will leverage data and samples from the AIDS Clinical Trials Group (ACTG) to investigate the ability of two plasma biomarkers, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), to discriminate between older PWH (over age 45 years) on antiretroviral therapy who develop cognitive impairment and those who remain free of cognitive impairment. These biomarkers are surrogates for neuroaxonal injury and astrocyte proliferation, respectively, and are actively under investigation for other neurological disorders, including cognitive decline in older people without HIV presenting to memory clinics. To provide more accurate estimates of plasma NfL and GFAP levels for clinical interpretations, the team will additionally determine the relationship between comorbidities frequently associated with cognitive function and plasma concentrations of these biomarkers in PWH on antiretroviral therapy. Data generated from this proposal will be used to expand the CHARMED model; the research team will then use the CHARMED model to assess the implications of the range of test characteristics for these two biomarkers and examine the impact and cost-effectiveness of a biomarker approach to diagnosis based on a range of costs per test among people aging with HIV.