Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function

作者：Yuankai Zhang, Xue Liu, Kerri L. Wiggins, Nuzulul Kurniansyah, Xiuqing Guo, Amanda Rodrigue, Wei Zhao, Lisa R. Yanek, Scott M. Ratliff, Achilleas Pitsillides, Juan Sebastian Aguirre Patiño, Tamar Sofer, Dan E. Arking, Thomas R. Austin, Alexa Beiser, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E. Curran, Lifang Hou, Timothy M. Hughes, Sharon L.R. Kardia, Lenore J. Launer, Daniel Levy, Thomas H. Mosley, Ilya M. Nasrallah, Stephen S. Rich, Jerome I. Rotter, Sudha Seshadri, Wassim Tarraf, Kevin A. González, Ramachandran S. Vasan, Kristine Yaffe, Paul Nyquist, Bruce M. Psaty, Charles DeCarli, Jennifer A. Smith, David C. Glahn, Héctor M. González, Joshua C. Bis, Myriam Fornage, Susan R. Heckbert, Annette L. Fitzpatrick, Chunyu Liu, Claudia L. Satizábal, for the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups, for the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups, Norma Aguilera, Seth A. Ament, Farah Ammous, Donna K. Arnett, Diane M. Becker, Joshua C. Bis, Elizabeth Blue, Eric Boerwinkle, Camille Breaux, Jan Bressler, Dima Chaar, MHI, Danielle Clarkson-Townsend, Brigidann Cooper, Josef Coresh, Adolfo Correa, Anita L. DeStefano, Jingzhong Ding, David W. Fardo, Annette L. Fitzpatrick, Myriam Fornage, Jennifer French, David C. Glahn, Héctor M. González, Einat Granot‐Hershkovitz, Patrick J. Hanly, Kathleen M. Hayden, Susan R. Heckbert, Scott Heemann, Steve Horvath, Karin F. Hoth, Timothy M. Hughes, Sidd Jaiswal, Xueqiu Jian, Yuriko Katsumata, Minjung Kho, Charles Kooperberg, Lenore J. Launer, Honghuang Lin, Elizabeth Litkowski, W. T. Longstreth, Alexandra Martin, Richard Mayeux, Julie Mikulla, Amy Miller, Biswapriya B. Misra, Thomas H. Mosley, Paul Nyquist, Jeff O’Connell, Michael Olivier, Gina M. Peloso, James A. Perry, Bruce M. Psaty, Shaun Purcell, Laura M. Raffield, Yugandi Ranaweera, Alex P. Reiner, Jerome Rotter, Muralidharan Sargurupremraj, Chloé Sarnowski, Claudia L. Satizábal, Gerard Schellenberg, Bonnie L Schoenbein, Sudha Seshadri, Lincoln M. P. Shade, Meghan I. Short, Jeannette Simino, Jennifer A. Smith, Mallorie Smith, Sylvia Smoller, Beverly Snively, Rachel Soemedi, Sophie Sokolow, Daune Thorington, Timothy A. Thornton, Lisa R. Yanek, Qiong Yang, Miao Yu, Habil Zare, Wei Zhao, Gonçalo R. Abecasis, Avinash Abhyankar, Micheala A. Aldred, Dan E. Arking, Allison E. Ashley‐Koch, Abraham Aviv, Kathleen Barnes, Emily Barron‐Casella, Stephanie L. Battle, Thomas W. Blackwell, Deepika Burkardt, Christina A. Castellani, Suzy Comhair, Brigidann Cooper, Adolfo Correa, Phyllis Crockett, Mariza de Andrade, Dawn L. DeMeo, Maria Rizzo DePaoli, Jun Ding, Christine Dobski, Serpil C. Erzurum, Samar Farha, Jessica L. Fetterman, Caitlin Floyd, Mao Fu, Amber Gist, Einat Granot‐Hershkovitz, C. Charles Gu, Scott Heemann, Ryan D. Hernandez, Yun Soo Hong, Yi‐Hsiang Hsu, Anne E. Justice, Leslie A. Lange, Dan Levy, Honghuang Lin, Chunyu Liu, Ryan J. Longchamps, Jiantao Ma, JoAnn Manson, Tammy Markus, Merry‐Lynn McDonald, Stephen T. McGarvey, Julie Mikulla, Courtney G. Montgomery, Rajeeva Musunuri, Jeff O’Connell, Richard Oppong, Nathan Pankratz, Yong Qian, Jerome Rotter, Jessica R Shaw, Albert V. Smith, Tamar Sofer, Elizabeth A. Streeten, Weihong Tang, Kent D. Taylor, Marilyn J. Telen, Shelby Thompson, Daune Thorington, Hemant K. Tiwari, Ann Walsh, Emily S. Wan, Cuicui Wang, Heming Wang, Penglong Wang, B. S. Weir, L. Keoki Williams, James G. Wilson, Shujie Xiao, Weiling Xu, Yu‐Chung Yang, Wei Zhao · 发表于：Neurology · 年份：2023 · DOI：10.1212/wnl.0000000000207157 · 被引用次数：36 · 研究领域：Mitochondrial Function and Pathology、Dementia and Cognitive Impairment Research、Alzheimer's disease research and treatments

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-sectio...