Abstract
Abstract Background Blood‐derived mitochondrial DNA copy number (mtDNA‐CN) is the proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA‐CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA‐CN and Alzheimer’s Disease (AD) and the underlying mechanisms of mitochondrial dysfunction in the pathogenesis of AD are still unclear. Method To investigate the causal relationship between mtDNA‐CN and AD, we performed two‐sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA‐CN and AD. Further, we estimated mtDNA‐CN using whole‐genome sequence data from blood samples of 1,521 ADNI participants and used a Cox proportional hazard model, adjusted for age, sex, and study phase, to assess the association between mtDNA‐CN and AD risk. The association of AD biomarkers measured in brain and plasma metabolites with mtDNA‐CN was evaluated using linear regression. We conducted causal mediation analysis to test the natural indirect effects of mtDNA‐CN change on AD risk through the significantly associated biomarkers and metabolites. Result MR analysis using a profile likelihood approach suggested a causal relationship between decreased blood‐derived mtDNA‐CN and increased risk of AD (OR = 0.71; P = 0.023). Survival analysis showed that decreased mtDNA‐CN was significantly associated with increased risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.0017). We also identified significant associations between mtDNA‐CN and brain glucose metabolism (β = 0.050; P = 0.047) and amyloid‐β (Aβ) (β = 0.069; P = 0.015) and CSF Aβ (β = ‐0.051; P = 0.048). Plasma Aβ was, however, not associated. Several lipid species, amino acids, biogenic amines, and inflammatory proteins in plasma were also significantly associated with mtDNA‐CN. Finally, causal mediation analyses showed that the effect of change in mtDNA‐CN on AD risk is mediated by plasma neurofilament light (β = ‐0.055; P = 0.010), glycine (β = 0.016; P = 0.044), and hexadecenoylcarnitine (β = ‐0.017; P = 0.049). Conclusion Our study indicates that mtDNA‐CN measured in blood is predictive of AD risk. Associations of mtDNA‐CN with Aβ in CSF and brain, but not plasma, suggest cross‐tissue regulation of mitochondria. Decreased mtDNA‐CN might increase AD risk through lipid and amino acid metabolism. These results also suggest potential development of mtDNA‐CN as a blood‐based biomarker.