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.