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

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.