PROJECT SUMMARY Neurovascular calcification is associated with cerebrovascular disease, with mild cognitive impairment (MCI), Alzheimer’s disease and related dementias (ADRD), but mechanisms are uncertain. To clarify how calcification harms neurocognitive functions, we focus on the relationship between regional brain volume and calcification of intracranial internal carotid arteries (iICAs), which are among the blood vessels with strongest ADRD involvement. Although both medial and intimal iICACs predict disease, how iICAC relates to age-related regional brain volume trajectories, MCI, and ADRD is unknown. We propose CT studies of iICAC in two native South American populations with high iICAC prevalence: the Tsimane/Moseten people of Bolivia. These forager-farmer populations with a non-industrial lifestyle have higher iICAC prevalence than US/EU populations, but far less brain volume decline with age. Tsimane lifestyle approximates that of our preindustrial past, whereas Moseten have partial exposure to the industrialized world and are thus closer to the US/EU along the industrialization continuum. In our first aim, we will develop automated, clinician-validated methods to segment, characterize and quantify iICAC. We will (1) distinguish medial from intimal iICAC, (2) calculate iICAC volumetrics & morphology, and (3) perform validation using gold-standard manual segmentations supervised by clinicians. In our second aim, we will determine how medial vs. intimal iICAC modifies age-dependent gray matter volume trajectory. We will segment gyri/sulci from head CT at resolutions approaching that of MRI. We will relate iICAC to gyral/sulcal volumes as a function of age and sex. In our third aim, we will quantify how medial/intimal iICAC acts on regional brain volumes to influence MCI and ADRD. The extent to which medial vs. intimal iICACs are associated with regional brain atrophy that reflects MCI/ADRD will be quantified in Tsimane/Moseten (N > 1200) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N > 800). Establishing the relationships linking iICAC to regional atrophy and to cognitive impairment status can help to understand the etiology and pathways whereby vascular disease risk operates on the risk of MCI and ADRD through brain atrophy. This project will also inform public health strategies to recommend preventive behaviors: should blood biomarkers of disease risk predict iICAC, this would help to establish how such biomarkers associate with ADRD. Proposed approaches could augment clinicians’ diagnostic armamentarium by providing information with predictive value on cognitive trajectories leading to ADRD. This is a unique opportunity as findings may generalize to other populations. CT methods will help to further the study of brain aging and ADRD in underprivileged populations with limited access to MRI. Project findings should also help to inform the high ADRD morbidity of US Native American populations.