Meta-Analysis

. 2023 May 2;100(18):e1930-e1943.

doi: 10.1212/WNL.0000000000207157. Epub 2023 Mar 16.

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

Yuankai Zhang¹, Xue Liu¹, Kerri L Wiggins¹, Nuzulul Kurniansyah¹, Xiuqing Guo¹, Amanda L Rodrigue¹, Wei Zhao¹, Lisa R Yanek¹, Scott M Ratliff¹, Achilleas Pitsillides¹, Juan Sebastian Aguirre Patiño¹, Tamar Sofer¹, Dan E Arking¹, Thomas R Austin¹, Alexa S Beiser¹, John Blangero¹, Eric Boerwinkle¹, Jan Bressler¹, Joanne E Curran¹, Lifang Hou¹, Timothy M Hughes¹, Sharon L R Kardia¹, Lenore J Launer¹, Daniel Levy¹, Thomas H Mosley¹, Ilya M Nasrallah¹, Stephen S Rich¹, Jerome I Rotter¹, Sudha Seshadri¹, Wassim Tarraf¹, Kevin A González¹, Vasan Ramachandran¹, Kristine Yaffe¹, Paul A Nyquist¹, Bruce M Psaty¹, Charles S DeCarli¹, Jennifer A Smith¹, David C Glahn¹, Hector M González¹, Joshua C Bis¹, Myriam Fornage¹, Susan R Heckbert¹, Annette L Fitzpatrick¹, Chunyu Liu¹, Claudia L Satizabal²; NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups

Collaborators, Affiliations

Collaborators

NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups:
Norma Aguilera, Seth Ament, Farah Ammous, Donna K Arnett, Diane Becker, Joshua Bis, Elizabeth Blue, Eric Boerwinkle, Camille Breaux, Jan Bressler, Dima Chaar, Mhi, Danielle Clarkson-Townsend, Brigidann Cooper, Josef Coresh, Adolfo Correa, Anita DeStefano, Jingzhong Ding, David Fardo, Annette Fitzpatrick, Myriam Fornage, Jennifer French, David Glahn, Hector Gonzalez, Einat Granot-Hershkovitz, Patrick Hanly, Kathleen Hayden, Susan Heckbert, Scott Heemann, Steve Horvath, Karin Hoth, Timothy Hughes, Sidd Jaiswal, Xueqiu Jian, Yuriko Katsumata, Minjung Kho, Charles Kooperberg, Lenore Launer, Honghuang Lin, Elizabeth Litkowski, Will Longstreth, Alexandra Martin, Richard Mayeux, Julie Mikulla, Amy Miller, Biswapriya Misra, Thomas Mosley, Paul Nyquist, Jeff O'Connell, Michael Olivier, Gina Peloso, James Perry, Bruce Psaty, Shaun Purcell, Laura Raffield, Yugandi Ranaweera, Alex Reiner, Jerome Rotter, Muralidharan Sargurupremraj, Chloé Sarnowski, Claudia Satizabal, Gerard Schellenberg, Bonnie L Schoenbein, Sudha Seshadri, Lincoln Shade, Meghan I Short, Jeannette Simino, Jennifer Smith, Mallorie Smith, Sylvia Smoller, Beverly Snively, Rachel Soemedi, Sophie Sokolow, Daune Thorington, Timothy A Thornton, Lisa Yanek, Qiong Yang, Miao Yu, Habil Zare, Wei Zhao, Goncalo Abecasis, Avinash Abhyankar, Micheala Aldred, Dan Arking, Allison Ashley-Koch, Abraham Aviv, Kathleen Barnes, Emily Barron-Casella, Stephanie Battle, Thomas Blackwell, Deepika Burkardt, Christina A Castellani, Suzy Comhair, Brigidann Cooper, Adolfo Correa, Phyllis Crockett, Mariza de Andrade, Dawn DeMeo, Maria Rizzo DePaoli, Jun Ding, Christine Dobski, Serpil Erzurum, Samar Farha, Jessica Fetterman, Caitlin Floyd, Mao Fu, Amber Gist, Einat Granot-Hershkovitz, C Charles Gu, Scott Heemann, Ryan Hernandez, Yun Soo Hong, Yi-Hsiang Hsu, Anne Justice, Leslie Lange, Dan Levy, Honghuang Lin, Chunyu Liu, Ryan Longchamps, Jiantao Ma, JoAnn Manson, Tammy Markus, Merry-Lynn McDonald, Stephen McGarvey, Julie Mikulla, Courtney Montgomery, Rajeeva Lochan Musunuri, Jeff O'Connell, Richard Oppong, Nathan Pankratz, Yong Qian, Jerome Rotter, Jessica R Shaw, Albert Vernon Smith, Tamar Sofer, Elizabeth Streeten, Weihong Tang, Kent D Taylor, Marilyn Telen, Shelby Thompson, Daune Thorington, Hemant Tiwari, Ann Walsh, Emily Wan, Cuicui Wang, Heming Wang, Penglong Wang, Bruce Weir, L Keoki Williams, James Wilson, Shujie Xiao, Weiling Xu, Yu-Chung Yang, Wei Zhao

Affiliations

¹ From 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.
² From 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. satizabal@uthscsa.edu.

PMID: 36927883
PMCID: PMC10159770
DOI: 10.1212/WNL.0000000000207157

Meta-Analysis

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

Yuankai Zhang et al. Neurology. 2023.

. 2023 May 2;100(18):e1930-e1943.

doi: 10.1212/WNL.0000000000207157. Epub 2023 Mar 16.

Authors

Collaborators

NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups:
Norma Aguilera, Seth Ament, Farah Ammous, Donna K Arnett, Diane Becker, Joshua Bis, Elizabeth Blue, Eric Boerwinkle, Camille Breaux, Jan Bressler, Dima Chaar, Mhi, Danielle Clarkson-Townsend, Brigidann Cooper, Josef Coresh, Adolfo Correa, Anita DeStefano, Jingzhong Ding, David Fardo, Annette Fitzpatrick, Myriam Fornage, Jennifer French, David Glahn, Hector Gonzalez, Einat Granot-Hershkovitz, Patrick Hanly, Kathleen Hayden, Susan Heckbert, Scott Heemann, Steve Horvath, Karin Hoth, Timothy Hughes, Sidd Jaiswal, Xueqiu Jian, Yuriko Katsumata, Minjung Kho, Charles Kooperberg, Lenore Launer, Honghuang Lin, Elizabeth Litkowski, Will Longstreth, Alexandra Martin, Richard Mayeux, Julie Mikulla, Amy Miller, Biswapriya Misra, Thomas Mosley, Paul Nyquist, Jeff O'Connell, Michael Olivier, Gina Peloso, James Perry, Bruce Psaty, Shaun Purcell, Laura Raffield, Yugandi Ranaweera, Alex Reiner, Jerome Rotter, Muralidharan Sargurupremraj, Chloé Sarnowski, Claudia Satizabal, Gerard Schellenberg, Bonnie L Schoenbein, Sudha Seshadri, Lincoln Shade, Meghan I Short, Jeannette Simino, Jennifer Smith, Mallorie Smith, Sylvia Smoller, Beverly Snively, Rachel Soemedi, Sophie Sokolow, Daune Thorington, Timothy A Thornton, Lisa Yanek, Qiong Yang, Miao Yu, Habil Zare, Wei Zhao, Goncalo Abecasis, Avinash Abhyankar, Micheala Aldred, Dan Arking, Allison Ashley-Koch, Abraham Aviv, Kathleen Barnes, Emily Barron-Casella, Stephanie Battle, Thomas Blackwell, Deepika Burkardt, Christina A Castellani, Suzy Comhair, Brigidann Cooper, Adolfo Correa, Phyllis Crockett, Mariza de Andrade, Dawn DeMeo, Maria Rizzo DePaoli, Jun Ding, Christine Dobski, Serpil Erzurum, Samar Farha, Jessica Fetterman, Caitlin Floyd, Mao Fu, Amber Gist, Einat Granot-Hershkovitz, C Charles Gu, Scott Heemann, Ryan Hernandez, Yun Soo Hong, Yi-Hsiang Hsu, Anne Justice, Leslie Lange, Dan Levy, Honghuang Lin, Chunyu Liu, Ryan Longchamps, Jiantao Ma, JoAnn Manson, Tammy Markus, Merry-Lynn McDonald, Stephen McGarvey, Julie Mikulla, Courtney Montgomery, Rajeeva Lochan Musunuri, Jeff O'Connell, Richard Oppong, Nathan Pankratz, Yong Qian, Jerome Rotter, Jessica R Shaw, Albert Vernon Smith, Tamar Sofer, Elizabeth Streeten, Weihong Tang, Kent D Taylor, Marilyn Telen, Shelby Thompson, Daune Thorington, Hemant Tiwari, Ann Walsh, Emily Wan, Cuicui Wang, Heming Wang, Penglong Wang, Bruce Weir, L Keoki Williams, James Wilson, Shujie Xiao, Weiling Xu, Yu-Chung Yang, Wei Zhao

Affiliations

¹ From 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.
² From 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. satizabal@uthscsa.edu.

PMID: 36927883
PMCID: PMC10159770
DOI: 10.1212/WNL.0000000000207157

Abstract

Background and objectives: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

Methods: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality.

Results: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

Discussion: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.

PubMed Disclaimer

Conflict of interest statement

B.M. Psaty serves on the Steering Committee of the Yale Open Data Access Project, funded by Johnson & Johnson. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Study Design and Data Contribution by Cohort**
The x-axis is the time interval in years between the blood draw and cognition/MRI measures. *Blood draw and cognitive function assessment were conducted at the same time in the HCHS/SOL. ARIC = Atherosclerosis Risk in Communities study; CARDIA = Coronary Artery Risk Development in Young Adults study; CHS = Cardiovascular Health Study; CN = copy number; FHS = Framingham Heart Study; GeneSTAR = Genetic Study of Atherosclerosis Risk; GENOA = Genetic Epidemiology Network of Arteriopathy Study; GOBS = Genetics of Brain Structure and Function Study; HCHS/SOL = Hispanic Community Health Study/Study of Latinos; MESA = Multi-Ethnic Study of Atherosclerosis; mtDNA = mitochondrial DNA.

**Figure 2. Forest Plots of the Association of mtDNA CN With General Cognitive Function per Cohort and Meta-analysis Results**
Covariates included age, sex, batch effect, self-reported race/ethnicity, the time between blood draw and cognitive evaluation, cohort-specific variables, and education. β is the estimated difference in standardized general cognitive function score per SD unit increment in mtDNA CN. (A) Cross-sectional analyses. (B) Prospective analyses. ARIC = Atherosclerosis Risk in Communities study; CARDIA = Coronary Artery Risk Development in Young Adults study; CHS = Cardiovascular Health Study; CN = copy number; FHS = Framingham Heart Study; GeneSTAR = Genetic Study of Atherosclerosis Risk; GENOA = Genetic Epidemiology Network of Arteriopathy Study; GOBS = Genetics of Brain Structure and Function Study; HCHS/SOL = Hispanic Community Health Study/Study of Latinos; MESA = Multi-Ethnic Study of Atherosclerosis; mtDNA = mitochondrial DNA.

**Figure 3. Forest Plots of the Sex-Specific Association of mtDNA CN With General Cognitive Function per Cohort and Meta-analysis Results**
Covariates included age, batch effect, self-reported race/ethnicity, the time between blood draw and cognitive evaluation, cohort-specific variables, and education. β is the estimated difference in standardized general cognitive function score per SD unit increment in mtDNA CN. (A) Cross-sectional analyses. (B) Prospective analyses. ARIC = Atherosclerosis Risk in Communities study; CARDIA = Coronary Artery Risk Development in Young Adults study; CHS = Cardiovascular Health Study; CN = copy number; FHS = Framingham Heart Study; GeneSTAR = Genetic Study of Atherosclerosis Risk; GENOA = Genetic Epidemiology Network of Arteriopathy Study; GOBS = Genetics of Brain Structure and Function Study; HCHS/SOL = Hispanic Community Health Study/Study of Latinos; MESA = Multi-Ethnic Study of Atherosclerosis; mtDNA = mitochondrial DNA.

**Figure 4. Forest Plots of the Age-Specific Association of mtDNA CN With General Cognitive Function per Cohort and Meta-analysis Results**
Covariates included age, sex, batch effect, self-reported race/ethnicity, the time between blood draw and cognitive evaluation, cohort-specific variables, and education. β is the estimated difference in standardized general cognitive function score per SD unit increment in mtDNA CN. (A) Cross-sectional analyses. (B) Prospective analyses. ARIC = Atherosclerosis Risk in Communities study; CARDIA = Coronary Artery Risk Development in Young Adults study; CHS = Cardiovascular Health Study; CN = copy number; FHS = Framingham Heart Study; GeneSTAR = Genetic Study of Atherosclerosis Risk; GENOA = Genetic Epidemiology Network of Arteriopathy Study; GOBS = Genetics of Brain Structure and Function Study; HCHS/SOL = Hispanic Community Health Study/Study of Latinos; MESA = Multi-Ethnic Study of Atherosclerosis; mtDNA = mitochondrial DNA.

**Figure 5. Forest Plots of the Race/Ethnicity-Specific Association of mtDNA CN With General Cognitive Function per Cohort and Meta-analysis Results**
Covariates included age, sex, batch effect, the time between blood draw and cognitive evaluation, cohort-specific variables, and education. β is the estimated difference in standardized general cognitive function score per SD unit increment in mtDNA CN. (A) Cross-sectional analyses. (B) Prospective analyses. ARIC = Atherosclerosis Risk in Communities study; CARDIA = Coronary Artery Risk Development in Young Adults study; CHS = Cardiovascular Health Study; CN = copy number; FHS = Framingham Heart Study; GeneSTAR = Genetic Study of Atherosclerosis Risk; GENOA = Genetic Epidemiology Network of Arteriopathy Study; GOBS = Genetics of Brain Structure and Function Study; HCHS/SOL = Hispanic Community Health Study/Study of Latinos; MESA = Multi-Ethnic Study of Atherosclerosis; mtDNA = mitochondrial DNA.

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

Collaborators

Affiliations

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

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