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Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites
Tong T, Zhu C, Farrell JJ, Khurshid Z, Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Neuroimaging Initiative, Martin ER, Pericak-Vance MA et al.. Alzheimer's research & therapy, 2024-10-23
Topic: Amyloid, tau and blood-test diagnosis
Background Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a 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 disease (AD) is unclear. Methods We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer's Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer's Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites. Results MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P Conclusions Our study indicates that mtDNA-CN measured in blood is predictive of AD and is associated with AD biomarkers including plasma NFL particularly in females. Further, we illustrate that decreased mtDNA-CN possibly increases AD risk through dysregulation of mitochondrial lipid metabolism and inflammation.
Key findings
- We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites.
- Results MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013).
- Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002).
- We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females.
- Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN.
Why it matters
Genetic analysis suggested that lower blood-derived mitochondrial DNA copy number is causally linked to higher Alzheimer disease risk and to conversion from mild cognitive impairment to Alzheimer disease. This points to mitochondrial function as a possible risk pathway, but it does not show that changing mitochondrial DNA copy number prevents or treats the disease.
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Study details
- Participants13,799
- Effect sizeOR = 0.68; HR = 0.80
- Evidence strengthLow
How this study scored 53/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer's research & therapy) |
| Journal's citation record | 1 / 4 | Alzheimer s Research & Therapy: journal h-index 146 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2024 — within 3 year(s) of the newest study here |
| Sample size | 4 / 4 | 13,799 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 26 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.5 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 3 / 6 | Cited 7.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 26 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Xiaoling Zhang: h-index 35 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Pennsylvania: institution h-index 1,859 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39444005) |
| Free to read | 2 / 2 | Free to read |
| Total | 53 / 100 | — |
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Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Tong, T., Zhu, C., Farrell, J. J., Khurshid, Z., Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Neuroimaging Initiative, et al. (2024). Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites. Alzheimer's research & therapy. https://doi.org/10.1186/s13195-024-01601-w
Vancouver
Tong T, Zhu C, Farrell JJ, Khurshid Z, Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Neuroimaging Initiative, et al. Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites. Alzheimer's research & therapy. 2024. doi:10.1186/s13195-024-01601-w. PMID: 39444005.
BibTeX
@article{tong2024-39444005,
author = {Tong, T. and Zhu, C. and Farrell, J. J. and Khurshid, Z. and {Alzheimer’s Disease Sequencing Project} and {Alzheimer’s Disease Neuroimaging Initiative} and Martin, E. R. and Pericak-Vance, M. A. and others},
title = {{Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites}},
journal = {Alzheimer's research \& therapy},
year = {2024},
doi = {10.1186/s13195-024-01601-w},
pmid = {39444005},
url = {https://doi.org/10.1186/s13195-024-01601-w}
}
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