Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of

Yuankai Zhang1, Xue Liu1, Kerri L Wiggins1

  • 1From the Department of Biostatistics (Y.Z., X.L., A.P., A.S.B., C.L.), School of Public Health, Boston University, MA; Cardiovascular Health Research Unit (K.L.W., J.C.B.), Department of Medicine, University of Washington, Seattle; Brigham and Women's Hospital (N.K., T.S.), Boston, MA; The Institute for Translational Genomics and Population Sciences (X.G., J.I.R.), Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance; Department of Psychiatry and Behavioral Sciences (A.L.R., D.C.G.), Boston Children's Hospital, MA; Department of Psychiatry (A.L.R., D.C.G.), Harvard Medical School, Boston Children's Hospital, MA; Department of Epidemiology (W.Z., S.M.R., S.L.R.K., J.A.S.), School of Public Health, University of Michigan, Ann Arbor; GeneSTAR Research Program (L.R.Y.), Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; School of Medicine (J.S.A.P.), Universidad de Los Andes, Bogotá, Colombia; Harvard Medical School (T.S.), Boston, MA; McKusick-Nathans Institute (D.E.A.), Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Epidemiology (T.R.A.), University of Washington, Seattle; Department of Neurology (A.S.B.), School of Medicine, Boston University, MA; Framingham Heart Study (A.S.B., D.L., S.S., V.R., C.L., C.L.S.), Framingham, MA; Department of Human Genetics and South Texas Diabetes and Obesity Institute (J. Blangero, J.E.C.), University of Texas Rio Grande, Brownsville; Human Genetics Center (E.B., J. Bressler), School of Public Health, The University of Texas Health Science Center at Houston; Human Genome Sequencing Center (E.B.), Baylor College of Medicine, Houston, TX; Department of Preventive Medicine (L.H.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Internal Medicine (T.M.H.), Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC; National Institute on Aging (L.J.L.), and Population Sciences Branch National Heart, Lung, and Blood Institute (D.L.), NIH, Bethesda, MD; Memory Impairment and Neurodegenerative Dementia (MIND) Center (T.H.M.), School of Medicine, University of Mississippi Medical Center, Jackson; Center for Biomedical Image Computing and Analytics (I.M.N.), Department of Radiology, University of Pennsylvania, Philadelphia; Center for Public Health Genomics (S.S.R.), University of Virginia School of Medicine, Charlottesville; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (S.S., C.L.S.), University of Texas Health Science Center at San Antonio; Institute of Gerontology & Department of Healthcare Sciences (W.T.), Wayne State University, Detroit, MI; Department of Neurosciences (K.A.G.) and Shiley-Marcos Alzheimer's Disease Center (H.M.G.), University of California, San Diego, La Jolla; Department of Medicine (V.R.), School of Medicine, and Department of Epidemiology, Boston University, MA; University of California, San Francisco (K.Y.); Department of Neurology (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle; Department of Neurology (C.S.D.), UC Davis, CA; Institute of Molecular Medicine (M.F.), McGovern Medical School; and Human Genetics Center (M.F.), School of Public Health, University of Texas Health Science Center at Houston; and Cardiovascular Health Research Unit and Department of Epidemiology (S.R.H.), and Departments of Family Medicine, Epidemiology, and Global Health (A.L.F.), University of Washington, Seattle.

Neurology
|March 17, 2023
PubMed
Abstract

Insights

Higher mitochondrial DNA (mtDNA) copy number (CN) in blood is linked to better cognitive function in adults. This association suggests mtDNA CN may be a biomarker for cognitive health, though causality is not yet established.

Area of Science:

  • Neuroscience
  • Genetics
  • Biomarkers

Background:

  • Mitochondrial DNA (mtDNA) copy number (CN) is implicated in neurodegenerative diseases.
  • The relationship between blood mtDNA CN and Alzheimer disease (AD) and AD-related dementia (AD/ADRD) endophenotypes requires further investigation.
  • This study examines mtDNA CN in relation to cognitive function and brain imaging in community-based samples.

Approach:

  • Utilized whole-genome sequencing data from 9 diverse cohorts in the Trans-Omics for Precision Medicine (TOPMed) program.
  • Assessed circulating mtDNA CN and its association with cognitive function and brain MRI measures (total brain, hippocampal, white matter hyperintensity volumes).
  • Employed cross-sectional and prospective analyses, meta-analyses, and Mendelian randomization (MR) to evaluate associations and causality.

Key Points:

  • Higher blood mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06).
  • Similar significant associations were found in prospective analyses, though with reduced magnitude.
  • No significant associations were observed between mtDNA CN and brain MRI measures; MR analyses did not support a causal link.

Conclusions:

  • Elevated mtDNA CN in blood correlates with better current and future general cognitive function in diverse US communities.
  • While causality is not confirmed, circulating mtDNA CN shows potential as a biomarker for cognitive function.
  • Further research is warranted to fully elucidate the causal role of mtDNA CN in cognitive health.

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