PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) are increasingly common neurodegenerative conditions that are fatal and progressive due to the lack of effective treatments. Mitochondria are intracellular organelles that are essential for energy metabolism and stress adaptation. Experimental models suggest that mitochondrial dysfunction occurs early in the pathogenesis of AD/ADRD, and damaged mitochondria have been observed in brain tissue of persons with AD/ADRD. Recent epidemiologic studies have linked aberrations in mitochondrial DNA (mtDNA) quantity and quality with several age-related outcomes, including risk of cardiovascular disease, kidney disease, and death, but their associations with cognitive function and dementia risk are not well-established. This AD/ADRD supplement will capitalize on an existing parent R01 to investigate the impact of blood-based measures of mtDNA quantity and quality on brain health among over 16,000 participants of four clinical studies: the Health, Aging and Body Composition Study (Health ABC, N=3,075); the Lifestyle Interventions and Independence for Elders Study (LIFE, N=1,755); the Systolic Blood Pressure Intervention Trial (SPRINT, N=9,361) and the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD, N=2,488). Our first Aim will determine whether mtDNA quantity, assessed by blood mtDNA copy number, is associated with risk of cognitive decline and dementia, independent of traditional clinical risk factors. Our second Aim will evaluate associations of mtDNA quality, assessed by inherited and acquired mtDNA mutations, with risk of cognitive decline and dementia using an innovative approach for integration of mutation burden across functional regions of the mitochondrial genome. These projects will: 1) generate novel hypotheses into the relationships between mitochondrial dysfunction and brain health; 2) advance mtDNA quantity and quality as candidate biomarkers of response to future interventions for AD/ADRD that promote mitochondrial health; and 3) inform enrichment of participants for future clinical trials of mitochondria-targeted therapies for treatment or prevention of AD/ADRD.