Project 1: Cognitive Function and Dementia—Abstract The greatest impact of Alzheimer’s disease and related dementias (ADRD) is likely to be experienced in low- and middle-income countries (LMICs). Sub-Saharan Africa, in particular, is projected to encounter a dramatic increase in dementia prevalence and there is a growing need for rigorous population-based studies of ADRD in this region. Health, Aging and Dementia in South Africa: A Longitudinal Study (HAALSI) addresses core issues in dementia epidemiology in older South Africans. We implement measures harmonized with the global Health and Retirement Study (HRS) and Harmonized Cognitive Assessment Protocol (HCAP) networks to enable cross-national comparisons of dementia and its risk factors. Project 1 (Cognitive Function and Dementia) leverages our deeply phenotyped HAALSI Agincourt cohort to identify causal pathways underlying cognitive trajectories and applies well-validated neuropsychological assessments to a nationally representative sample. These data will provide the first national estimates of dementia prevalence in South Africa. We do this through tightly coordinated work across four overlapping cohorts. Our original HAALSI Agincourt cohort comprised 5059 respondents ≥40 years of age, for whom we collected three waves of data; this renewal will add two additional waves. HAALSI-HCAP Agincourt (n≈700) is an enriched subcohort that adds detailed neuropsychological testing, neuroimaging, and blood biomarkers of ADRD; this renewal adds one additional wave of HAALSI-HCAP Agincourt (wave 3). We propose to field a new, nationally representative study of 4500 men and women (plus partners) and a HAALSI-HCAP National survey (n≈624). Project 1 has 3 aims. Aim 1 focuses on characterizing the incidence and progression of mild cognitive impairment (MCI) and dementia in relation to neurodegeneration and ADRD neuropathology in the enriched Agincourt-HCAP cohort. We examine longitudinal change in magnetic resonance imaging (MRI) markers of brain aging and incorporate plasma markers of ADRD (i.e., Ab, p-tau, NfL, GFAP) to assess associations with dementia symptoms. In Aim 2, we refine and validate the HAALSI Global Cognitive Screen, HAALSI-HCAP, and HAALSI dementia algorithms for South African nationwide surveys of dementia. We collaborate with Project 4 to conduct a baseline National HAALSI-HCAP wave to generate national prevalence estimates for dementia and MCI. In Aim 3, we examine the impact of social factors, including novel indicators of educational quality and social connection on participants’ cognitive function and change trajectories. We explore informal educational experiences of special relevance in the context of rapid social changes in South Africa, including self-taught literacy and effects of children’s educational attainment on cognition in older parents. Optimizing all four cohorts (HAALSI Agincourt, HAALSI-HCAP Agincourt, HAALSI National, HAALSI-HCAP National) we identify distinct biologi...