|Title||Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||Zhang, Y, Liu, X, Wiggins, KL, Kurniansyah, N, Guo, X, Rodrigue, AL, Zhao, W, Yanek, LR, Ratliff, SM, Pitsillides, A, Patiño, JSebastian, Sofer, T, Arking, DE, Austin, TR, Beiser, AS, Blangero, J, Boerwinkle, E, Bressler, J, Curran, JE, Hou, L, Hughes, TM, Kardia, SLR, Launer, LJ, Levy, D, Mosley, TH, Nasrallah, IM, Rich, SS, Rotter, JI, Seshadri, S, Tarraf, W, González, KA, Ramachandran, V, Yaffe, K, Nyquist, PA, Psaty, BM, DeCarli, CS, Smith, JA, Glahn, DC, Gonzalez, HM, Bis, JC, Fornage, M, Heckbert, SR, Fitzpatrick, AL, Liu, C, Satizabal, CL|
|Corporate Authors||NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups|
|Date Published||2023 May 02|
|Keywords||Aged, Alzheimer Disease, Brain, Cognition, Cross-Sectional Studies, DNA Copy Number Variations, DNA, Mitochondrial, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Prospective Studies|
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 (
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.
|Grant List||R01 AG048642 / AG / NIA NIH HHS / United States |
R35 AG071916 / AG / NIA NIH HHS / United States
RF1 AG054548 / AG / NIA NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 AG059727 / AG / NIA NIH HHS / United States