Mitochondrial haplogroups, but not heteroplasmy, are associated with midlife cognitive function

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INTRODUCTION: Mitochondrial DNA (mtDNA) variation may influence cognitive performance, but prior findings are inconsistent. METHODS: We analyzed data from 2308 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, assessing heteroplasmy (mtHz) burden and haplogroups (mtHg) from blood-derived mtDNA at three timepoints and cognitive function across multiple domains. Multivariate linear regression models and multivariate linear mixed models adjusted for age, sex, education, and race. RESULTS: MtDNA heteroplasmy burden and count were not associated with cognitive performance. However, mtHgs in macro-mtHg L were linked to poorer cognitive outcomes, particularly in processing speed and global cognition in cross-sectional and longitudinal analyses. Associations remained significant after adjusting for social determinants of health (SDOH) or APOE ε4, comorbidities, and lifestyle variables. DISCUSSION: The mtDNA variation, especially mtHgs, may play a role in influencing cognitive trajectories, warranting further research on its role in cognitive aging. HIGHLIGHTS: Heteroplasmy burden was not associated with cognitive performance at midlife. Haplogroups were associated with cognitive outcomes at midlife. Longitudinal analysis revealed that haplogroups are associated with cognitive trajectories.

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