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

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39007867
PMC11345514
The journals of gerontology. Series A, Biological sciences and medical sciences
Sept. 1, 2024
Michelle C Odden3, Yongmei Li3, Vasantha Jotwani7 4, Sylvie Dobrota3, Annabel X Tan3, Steven R Cummings1 2, Michael G Shlipak7 4, Rebecca Scherzer7 4, Joachim H Ix6, Marion S Buckwalter5, Gregory J Tranah1 2
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  • 1
    California Pacific Medical Center Research Institute, San Francisco, California, USA.
  • 2
    Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
  • 3
    Department of Epidemiology and Population Health, Stanford School of Medicine, Stanford, California, USA.
  • 4
    Department of Medicine, University of California San Francisco, San Francisco, California, USA.
  • 5
    Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, California, USA.
  • 6
    Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, California, USA.
  • 7
    Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Health Care System, San Francisco, California, USA.
Male, Cognition, Aging, Genetic Variation, Humans, Female, Aged, Aged, 80 and over, DNA, Mitochondrial, White, Black or African American
R01-AG028050, R01 NR012459, R01 HL151564
Odden MC, Li Y, Jotwani V, Dobrota S, Tan AX, Cummings SR, Shlipak MG, Scherzer R, Ix JH, Buckwalter MS, Tranah GJ. Joint and Individual Mitochondrial DNA Variation and Cognitive Outcomes in Black and White Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences. 2024 Sep 1.

Abstract

BACKGROUND: 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 2 large aging studies to identify variants related to cognitive function. METHODS: Participants included self-reported Black and White adults aged ≥70 years in the Lifestyle Interventions and Independence for Elders (LIFE; N = 1 319) and Health Aging and Body Composition (Health ABC; N = 788) studies. Cognitive function was measured by the Digit-Symbol Substitution Test (DSST), and the Modified Mini-Mental State Examination (3MSE) at baseline and over follow-up in LIFE (3.6 years) and Health ABC (10 years). We examined the 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 <.05 was considered statistically significant. RESULTS: 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. CONCLUSIONS: Among Black and White adults, oxidative phosphorylation Complex I variants were associated with cognitive function.