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.

Methods: 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).

Results: 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.

Discussion: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.

Research in context: 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 riskAD genetic liability is causally associated with higher mtDNAcn, possibly as a compensatory responsemtDNAcn is a potential early biomarker of mitochondrial dysfunction in AD/PD.