Various forms of chronic distress have been linked with premature aging, and development of cardiometabolic diseases (CMD), which are leading causes of death for older adults. Both chronic distress and CMD conditions are strongly linked with risk of Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD). While metabolic changes affecting vascular health are proposed as a key pathway driving the relationship between chronic distress and major diseases of aging, understanding of molecular mechanisms underlying such metabolic changes is limited. High-throughput technologies permit simultaneous measurement of hundreds of metabolites in plasma (“metabolomics”) and provide a broad picture of an individual’s metabolic profile. In our first funding cycle, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS)-based metabolomic score of chronic distress (anxiety and depression), in independent data sets of largely non-Hispanic White women; this score was associated with higher risk of incident CMD. In this renewal, using cutting edge metabolomic and biostatistical approaches along with several additional cohort studies, we propose to extend our initial findings and address the following specific aims: (1) Strengthen our existing chronic distress metabolite-score by adding novel, previously unknown metabolites strongly associated with the distress phenotype, and biochemically identify these validated but unknown metabolites to provide new mechanistic insight; (2) Assess our chronic distress metabolomic score (and its components) in key populations including African-American (AA) and Hispanic men and women and White men, and optimize the score in each population. We will also evaluate associations of the score (and components) with CMD and secondarily AD/ADRD risk in AA men and women, White men, and preliminarily in Hispanic men and women, and (3) Evaluate if chronic distress influences the distress-related metabolite score using causal methods and evaluate the distress-metabolite score as a potential mediator of the relationships of chronic distress with CMD risk and secondarily with AD/ADRD risk. We will achieve our aims by leveraging the robust data resources of five prospective studies: the Jackson Heart Study (n=5,306; 100% AA men and women), the Multi-Ethnic Study of Atherosclerosis (n=6,814; 39% White, 28% AA, 22% Hispanic, 12% Asian-American men and women), the Nurses’ Health Study (NHS; n=121,700, 98% White women), the Women’s Health Initiative (n=161,808 women; 18% non-White), PREDIMED (n=7,447; White men and women). Each cohort has similarly assessed chronic distress, blood metabolomic profiles, relevant covariates, CMD and dementia risk outcomes over up to 20 years of follow-up. NHS and MESA also have genetics data and repeated metabolomics measures. This work will extend our understanding of biologic pathways underlying chronic distress and their association with subsequent CMD and dementia risk amo...