Clinical Spectrum and Societal Impact of Cognitive Impairment, Alzheimer's and Related Dementias among people with HIV in Uganda

As people living with HIV (PWH) reach older age, determining their risk for mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRDs) is emerging as a major public health priority. Because HIV is relatively rare in the United States, particularly in the elderly, data in this area have largely been limited to young populations and lacked large samples with brain imaging and biomarkers to determine disease phenotypes. Moreover, social and clinical health predictors of MCI/ADRD differ meaningfully in PWH, so risk factors and their impact on households cannot be extrapolated from other populations. To respond to these gaps, we will leverage a team of experts in HIV epidemiology, diagnosis and phenotyping of MCI/ADRDs with fluid and imaging biomarkers, and machine learning (ML), and a large and well-established cohort of older people with HIV. Preliminary data generated by our team include neuropsychological screening of 300 older virologic suppressed PWH in Uganda (mean age >60), and 300 demographically similar people without HIV, showing that >30% of PWH have characteristics of MCI and that brain MRI and ML techniques add critical phenotyping data to standard batteries. Four specific aims are proposed: Aim 1: Determine the prevalence and classification of MCI/ADRDs (1A) and compare trajectories of cognitive performance (1B) between older PWH and similar people without HIV. Comprehensive neuropsychological assessments will be completed in older adults with and without HIV in the cohort (n=600) annually during years 1-4. MCI/ADRDs will be identified using multi-disciplinary case consensus criteria to provide diagnoses and underlying etiologies. Aim 2: Identify pathophysiologic contributors to MCI/ADRDs in older adults through deep phenotyping with novel plasma biomarkers and neuroimaging. Assessments will include Aβ42/Aβ40, p-tau217, GFAP, and NfL biomarkers and brain MRIs to characterize phenotypes. Aim 3: Estimate the psychosocial and economic impacts of MCI/ADRDs on adult household members. We will conduct in-depth interviews (n~40, Aim 3A) to learn about lived experiences of caregivers, and quantitative surveys (Aim 3B) to all adult household members of the cohort (n~1800) on employment and resource use, caregiving burden, quality of life, stigma, social participation, loneliness, and mental health. We will compare participants by the presence vs absence of MCI/ADRDs in the household. Aim 4: Discover and validate novel, multilevel mechanistic models of MCI/ADRDs among older PWH by employing ML methods with the full array of data collected in Aims 1-3. We will determine which combinations of highly dimensional features reliably classify individuals according to MCI/ADRDs profiles. Completing these aims will advance our understanding of MCI/ADRDs epidemiology among older PWH. In doing so, it will lay the foundation for diagnostic and intervention efforts to address research priorities for PWH in the United States and beyond. Project Number: 1R01AG087790-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: MARK SIEDNER | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $738,105 | Activity Code: R01 | Study Section: HIV Comorbidities and Clinical Studies Study Section[HCCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11187545