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

About This Grant

ABSTRACT As over 25 million people living with HIV (PWH) in sub-Saharan Africa (sSA) 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. Although neuropsychological testing data exist, it has been limited to young populations and lacked specialist evaluations, brain imaging and biomarkers to determine disease phenotypes and underlying etiologies. Moreover, social and clinical health determinants differ meaningfully in sSA, so risk factors for MCI/ADRDs and their impact on households cannot be extrapolated from other populations. This proposal is led by experts in the epidemiology of HIV in sSA, diagnosis and deep phenotyping of MCI/ADRDs with fluid and imaging biomarkers, and machine learning (ML) methods to elucidate mechanisms. 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 in Uganda and demographically 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 in Uganda 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 in Uganda. 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 and its societal impacts in Uganda. In doing so, it will lay the foundation for diagnostic, intervention, and capacity-building efforts to address NIA research priorities.