PROJECT SUMMARY / ABSTRACT This competitive renewal of “MESA-MIND” (R01AG058969) is a cooperative and multi-disciplinary project ideally positioned to fill critical gaps in our understanding of both the vascular contributions to cognitive impairment and dementia (VCID) in context of Alzheimer’s disease (AD) and related disorders (ADRD) and the noted the health disparities in VCID and AD/ADRD. This project is an extension of the Multi-Ethnic Study of Atherosclerosis (MESA), a large multi-ethnic cohort of 6814 adults now 65 and older (self-reported: 38% White, 28% Black, 22% Hispanic, and 12% Chinese Americans) with deep subclinical vascular phenotyping and stored plasma over the past two decades. Through initiation of MESA-MIND’s cognitive and imaging visits, we have demonstrated excellent feasibility to recruit MESA participants into a multimodal and multilingual ADRD research study more than 15 years after MESA baseline. The primary focus of MESA-MIND remains to define the subclinical vascular contributions to changes in AD/ADRD biomarkers and cognitive phenotypes of impairment. In MESA-MIND, we have shown that subclinical biomarkers of arteriosclerosis and atherosclerosis were associated with imaging biomarkers (MRI and PET), cognitive decline, and cognitive impairment. These peripheral vascular and imaging biomarkers of vascular disease tend to be higher in men, as well as self-reported Black and Hispanic older adults; differences that were partially explained by social determinants of health. MESA has recently built the infrastructure to define the temporal sequence of molecular dysregulation with longitudinal plasma AD biomarkers and ‘omics data over two decades. This renewal cycle seeks to make major strides in our mechanistic understanding of structural, functional, and molecular drivers of “subclinical VCID” by: (1) leveraging MESA’s longitudinal and extensive subclinical vascular biomarkers paired with recent advancements in high-throughput plasma AD biomarkers, proteomics and metabolomics technologies applied to MESA and (2) expanding these data resources through two new exams (“MIND C” and “MIND D”) over the next 5 years. These new resources will enable examination of the molecular (genomic, proteomic, and metabolomic) aspects shared by vascular disorders, AD biomarkers, and cognitive phenotypes as well as the temporal sequence of transition from subclinical disease to clinical phenotype. Each research question in MESA-MIND is designed to consider the consistency of subgroup analyses by gender, racial, and ethnic groups to characterize the health disparities in VCID/AD/ADRD in the context of social determinants of health.