Logo image
Back
Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function
Journal article   Open access   Peer reviewed

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

Yuankai Zhang, Xue Liu, Kerri L Wiggins, Nuzulul Kurniansyah, Xiuqing Guo, Amanda L Rodrigue, Wei Zhao, Lisa R Yanek, Scott M Ratliff, Achilleas Pitsillides, …
Neurology, Vol.100(18), pp.e1930-e1943
05/02/2023
DOI: 10.1212/WNL.0000000000207157
PMCID: PMC10159770
PMID: 36927883
url
https://europepmc.org/articles/pmc10159770View
Published (Version of record) Open Access

Abstract

Background and objectivesPrevious 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.MethodsWe 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.ResultsWe 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.DiscussionHigher 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.
 Aging Brain Brain Disorders Dementia DNA Genetics Magnetic Resonance Imaging Mental Health 4.1 Discovery and preclinical testing of markers and technologies Acquired Cognitive Impairment Aged Alzheimer Disease Alzheimer's Disease Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Biomedical and Clinical Sciences Clinical Research Clinical Sciences Cognition Cognitive Sciences Cross-Sectional Studies Detection DNA Copy Number Variations Female Good Health and Well Being Humans Male Middle Aged Mitochondrial Mitochondrial and Neurocognitive Working Groups Neurodegenerative Neurological Neurology & Neurosurgery Neurosciences NHLBI Trans-Omics for Precision Medicine (TOPMed) program Prospective Studies screening and diagnosis

Details

Metrics

17 Record Views
22 Times Cited - Web of Science
Logo image