Evaluating the causal effect of mitochondrial dysfunction on Alzheimer’s and Parkinson’s disease using Polygenic Risk Scores and Mendelian Randomization

INTRODUCTION Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with AD and PD. We integrate genetic correlation, Polygenic Risk Scores (PRS), and Mendelian Randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWAS) may distort these causal estimates.

Using GWAS of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the AD Genetics Consortium (N=27,383), and applied MR methods including Latent Heritable Confounder MR (LHC-MR).

Across the four mtDNAcn GWAS, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRS analysis showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk.

Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect. Systematic Review Mitochondrial dysfunction, measured by mitochondrial DNA copy number (mtDNAcn), has been linked to Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, Mendelian randomization (MR) studies on this relationship have shown inconsistent results, have not applied advanced MR methods that address prior limitations, or examined study-specific biases. Interpretation Using genetic correlations, polygenic scores, and Mendelian Randomization, we triangulated evidence across complementary methods. We found that results varied depending on the dataset (e.g., clinically diagnosed AD vs. family history of AD) and study design factors such as mtDNAcn measurement techniques. Despite these biases, higher mtDNAcn was consistently associated with a lower risk of AD and PD, supporting a mitochondrial mechanism in both diseases. Future directions Our findings highlight mtDNAcn as a potential biomarker for AD/PD, emphasizing the importance of measurement methods. Future research is needed to explore the biological pathways underlying this relationship. Highlights Genetically predicted higher mtDNAcn is causally associated with lower AD and PD risk AD genetic liability is causally associated with higher mtDNAcn, possibly as a compensatory response mtDNAcn is a potential early biomarker of mitochondrial dysfunction in AD/PD Competing Interest Statement The authors have declared no competing interest. Funding Statement AC is supported by R35AG071916 SJA is supported by the Alzheimer's Association (AARF-20-675804). C.J. is supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH), project number ZO1 AG000534, as well as the National Institute of Neurological Disorders and Stroke (NINDS). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. H.M.W. is supported by the Margaret Peg McLaughlin and Lydia A. Walker Opportunity Fund, the University of Kansas Alzheimer's Disease Center P30AG072973, R01AG078186, and by the Alzheimer's Association 23AARG-1023294 RHS and HMW are supported by AG072973. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵* Co-first authors Data Availability All statistical analyses were conducted using R (v4.3.0). The analysis code is publicly available at: https://github.com/AndrewsLabUCSF/Brian-Estimating-Causality-mtDNAcn-on-Alzheimer/tree/aadrita_mtdnacn. The original summary statistics are available at the following websites: https://dss.niagads.org/datasets/ng00075/, https://www.ebi.ac.uk/gwas/publications/35379992, https://pmc.ncbi.nlm.nih.gov/articles/PMC8422160/#S15, https://www.ebi.ac.uk/gwas/publications/27863252, https://www.ebi.ac.uk/gwas/publications/35023831, https://link.springer.com/article/10.1007/s00439-020-02249-w#data-availability,