Association of mitochondrial DNA copy number with brain MRI and cognitive function in the TOPMed Program

Background Mitochondria are the main energy source for normal neuronal functions. Mitochondrial DNA (mtDNA) copy number (CN), a measure of mtDNA levels in the cell, correlates with cellular energy generating capacity and metabolic status. Previous studies have observed a significant decrease of circulating cell‐free mtDNA content in the cerebrospinal fluid of patients with Alzheimer's disease (AD). However, it is unknown whether mtDNA CN circulating in the blood is related to AD endophenotypes. We aimed to investigate the cross‐sectional association of mtDNA CN with MRI markers of abnormal brain aging and cognitive function. Method We included dementia‐free, multiethnic participants from seven population‐based cohorts with whole‐genome sequencing as part of the Trans‐Omics for Precision Medicine (TOPMed) program. The average mtDNA CN in whole blood was estimated as twice the ratio of the average coverage of mtDNA to the average coverage of the nuclear DNA using fastMitoCalc from mitoAnalyzer. Brain MRI markers included total brain volume, hippocampal volume, and white matter hyperintensities. General cognitive function was derived from at least three distinct cognitive domains using principal component analysis. We related mtDNA CN to AD endophenotypes assessed within 5 years of blood draw per cohort and further performed random‐effects or sample size‐weighted meta‐analyses. Models were adjusted for demographics and vascular risk factors. Result Higher mtDNA CN was significantly associated with better general cognitive function (P‐values