PROJECT SUMMARY Almost half of all people diagnosed with HIV in the United States are aged 50 or older, and they are at increased risk for dementia and multimorbidity. Dementia is of major clinical policy concern because it results in both inexorable clinical decline and extremely high costs of care. People with HIV are at particularly high risk because they often have major risk factors for the development of traditional etiologies of dementia, such as Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD), and they also have a risk of HIV-associated neurocognitive disease (HAND) despite sustained virologic suppression. Depression, cardiovascular disease (CVD), and HIV are known to have potent synergies that contribute to the development of dementia. These comorbidities are modifiable risk factors for dementia that are highly prevalent, known to be undertreated in people with HIV, and likely to be clinically and economically important targets for prevention and management. The overall goal of this proposal is to provide an evidence-based approach for prioritizing and advocating for interventions to improve the quality of life and reduce morbidity and mortality among people aging with HIV. The benefits of reducing the burden of depression and CVD among people with HIV may currently be underestimated, given that concomitant benefits related to multimorbidity are often not captured due to short durations of observational or trial data. Determining which interventions are most clinically effective and cost- effective is critically important to understand so that people aging with HIV can benefit from strategies to reduce their risk of dementia and multimorbidity as they age. We propose to: 1) develop the Cognitive impairment, HIV, Aging, heaRt, MEntal health, and Dementia (CHARMED) Model, including populating the model with clinical and outcomes data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and nationally-representative cost data; 2) project clinical and economic outcomes of people aging with HIV; and 3) perform cost-effectiveness analyses of targeted interventions to reduce the burden of depression and CVD and to quantify the resultant reduction in dementia and multimorbidity. This proposal comprises a unique collaboration of experts in methods that are complementary and essential to complete the research aims: clinical expertise, epidemiology of people aging with HIV, costing, simulation modeling, and cost-effectiveness analysis. The proposed innovative multimorbidity model will be the first to include these important comorbidities that are highly prevalent, demonstrate synergies that contribute to dementia, and are amenable to treatment. The model structure and parameterization can both be revised with the emergence of updated data and improved understanding of the synergies and pathophysiology. This simulation modeling approach will allow for analyses of clinical and policy questions t...