Overall—Abstract Adults in South Africa are surviving to older ages, yet the burden and risk factors of aging-related diseases, particularly dementia and Alzheimer’s disease, remains poorly defined. By 2050, more than 75% of global dementia cases are projected to occur in low- and middle-income countries (LMICs). The proposed renewal of the Health, Aging and Dementia in South Africa: A Longitudinal Study (HAALSI) Program includes four tightly integrated projects supported by three cores that together will reveal interrelationships among common chronic diseases and other risk factors of cognitive impairment and dementia in South Africa. Each project rests on a common platform of individual surveys, cognitive assessments, biomarker collection, and mortality ascertainment, with additional measures specific to each project. In previous funding cycles (2014-2022), we successfully collected three waves of HAALSI Agincourt data in 5059 men and women ≥40 years of age, achieving response rates of 86-94% among living cohort members. We also collected two waves of data under the Harmonized Cognitive Assessment Protocol (HCAP) at 3-year intervals. For this renewal application, the HAALSI Program will continue following the HAALSI Agincourt cohort (Aim 1), including original enrollees and a refresher sample of 1898, 40- to 49-year-olds, for a total of 13 years of longitudinal data. We will conduct a third HCAP wave on a subsample of the HAALSI Agincourt cohort, with expanded biomarker, neuroimaging, and clinical assessments to understand interactions among cognitive impairment/dementia, HIV infection, and cardiometabolic disorders (CMDs). In Aim 2, we will identify biological, social, and economic predictors of mortality and dementia, and assess disease incidence and changes in physical and cognitive function in the HAALSI Agincourt cohort. In addition, in Aim 3, we will pilot and launch a nationally representative cohort study of 4500 people ≥40 years of age and their partners (approximately 7200 total) using approaches from the HAALSI Agincourt survey; of these, approximately 624 will also undergo the HCAP. The HAALSI National survey will enable us to estimate the prevalence of dementia and other aging-related conditions, and their cross-sectional associations with socioeconomic, behavioral, and health utilization exposures. We will use innovative transportability methods to assess the alignment of diseases in the rural Agincourt community with the national level. In Aim 4, we will evaluate the health impacts of public health and social policies developed to improve healthy aging, specifically those aimed at reducing salt intake, and increasing financial security of older adults, families, and individuals with disabilities. Finally, in Aim 5, we will maximize collaborations with HRS sister studies, H3Africa and DS-I Africa projects, enabling cross-country comparisons and studies at the level of population genetics. Together, the HAALSI Program will produce ...