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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.
Glossary
- AD=
- Alzheimer disease;
- ADRD=
- AD-related dementia;
- ARIC=
- Atherosclerosis Risk in Communities;
- CARDIA=
- Coronary Artery Risk Development in Young Adults;
- CHS=
- Cardiovascular Health Study;
- CN=
- copy number;
- FHS=
- Framingham Heart Study;
- GeneSTAR=
- Genetic Study of Atherosclerosis Risk;
- GENOA=
- Genetic Epidemiology Network of Arteriopathy;
- GOBS=
- Genetics of Brain Structure and Function Study;
- GWAS=
- genome-wide association study;
- HCHS/SOL=
- Hispanic Community Health Study/Study of Latinos;
- IVW=
- inverse-variance weighted;
- LD=
- linkage disequilibrium;
- MESA=
- Multi-Ethnic Study of Atherosclerosis;
- MR=
- mendelian randomization;
- mtDNA=
- mitochondrial DNA;
- qPCR=
- real-time PCR;
- SNV=
- single nucleotide variation;
- TOPMed=
- Trans-Omics for Precision Medicine;
- WES=
- whole-exome sequencing;
- WGS=
- whole-genome sequencing;
- WMH=
- white matter hyperintensity
Footnotes
↵Coinvestigators are listed at links.lww.com/WNL/C692.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Associate Editor Linda Hershey, MD, PhD, FAAN.
- Received June 29, 2022.
- Accepted in final form January 20, 2023.
- 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.
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