Joint and Individual Mitochondrial DNA Variation and Cognitive Outcomes in Black and White Older Adults.

Abstract

Mitochondrial dysfunction manifests in neurodegenerative diseases and other age-associated disorders. In this study, we examined variation in inherited mitochondrial DNA (mtDNA) sequences in Black and White participants from two large aging studies to identify variants related to cognitive function. Participants included self-reported Black and White adults aged ≥ 70 years in the Lifestyle Interventions and Independence for Elders (LIFE; N=1319) and Health Aging and Body Composition (Health ABC; N=7888) studies. Cognitive function was measured by the digit-symbol substitution test (DSST), and the Modified Mini-Mental State Exam (3MSE) at baseline and over follow-up in LIFE (3.6 years) and Health ABC (10 years). We examined joint effects of multiple variants across 16 functional mitochondrial regions with cognitive function using a sequence kernel association test. Based on these results, we prioritized meta-analysis of common variants in Black and White participants using mixed effects models. A Bonferroni adjusted p-value of <0.05 was considered statistically significant. Joint variation in subunits ND1, ND2, and ND5 of Complex I, 12S RNA, and hypervariable region (HVR) were significantly associated with DSST and 3MSE at baseline. In meta-analyses among Black participants, variant m.4216T>C, ND1 was associated with a faster decline in 3MSE, and variant m.462C>T in the HVR was associated with a slower decline in DSST. Variant m.5460G>C, ND2 was associated with slower and m.182C>T in the HVR was associated with faster decline in 3MSE in White participants. Among Black and White adults, oxidative phosphorylation Complex I variants were associated with cognitive function.