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Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer's disease: a multi-omics Mendelian randomization study
Zhang XX, Wei M, Wang HR, Hu YZ, Sun HM, Jia JJ.. Journal of translational medicine, 2024-10-03
Topic: Amyloid, tau and blood-test diagnosis
Background Mitochondrial dysfunction (MD) is increasingly recognized as a key pathophysiological contributor in Alzheimer disease (AD). As differential MD genes expression may serve as either a causative factor or a consequence in AD, and expression of these genes could be influenced by epigenetic modifications or interact with inflammatory cytokines, hence, the precise role of MD in AD remains uncertain. Methods Meta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD. We utilized three-step SMR to analyze the AD genome-wide association study summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs from the blood and brain tissues, respectively. Through SMR and colocalization analysis, we further explored the interactions between brain eQTLs and inflammatory cytokines. Results Five datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes. Among these, seven genes from blood samples such as NDUFS8 and SPG7 and thirty-two genes from brain tissue including CLU and MAPT were identified as candidate AD-causal MD genes and regulated by methylation level. Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor. Conclusions This study highlighted that the AD-causal MD genes could be regulated by epigenetic changes and interact with inflammatory cytokines, providing evidence for AD prevention and intervention.
Key findings
- Methods Meta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD.
- Results Five datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes.
- Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor.
Why it matters
Combining brain gene-expression data with genetic (Mendelian randomization) methods, this study identified mitochondrial-function genes that may play a causal role in Alzheimer's, such as NDUFS8 and SPG7 in blood and CLU and MAPT in brain, and found them influenced by DNA methylation. Some also interacted with inflammatory molecules including interleukin-18. These computational findings suggest targets for prevention and treatment research rather than ready interventions.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 57/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of translational medicine) |
| Journal's citation record | 2 / 4 | Journal of Translational Medicine: journal h-index 190 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” 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 | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| Times cited | 3 / 7 | Cited 24 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.0 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 3 / 6 | Cited 5.7× 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 24 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Jianjun Jia: h-index 32 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Chinese PLA General Hospital: institution h-index 413 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39363202) |
| Free to read | 2 / 2 | Free to read |
| Total | 57 / 100 | — |
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Read the original
- DOI: 10.1186/s12967-024-05680-z
- PubMed: 39363202
- Original source →
- Free full text: Journal of Translational Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Zhang, X. X., Wei, M., Wang, H. R., Hu, Y. Z., Sun, H. M., & Jia, J. J. (2024). Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer's disease: a multi-omics Mendelian randomization study. Journal of translational medicine. https://doi.org/10.1186/s12967-024-05680-z
Vancouver
Zhang XX, Wei M, Wang HR, Hu YZ, Sun HM, Jia JJ. Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer's disease: a multi-omics Mendelian randomization study. Journal of translational medicine. 2024. doi:10.1186/s12967-024-05680-z. PMID: 39363202.
BibTeX
@article{zhang2024-39363202,
author = {Zhang, X. X. and Wei, M. and Wang, H. R. and Hu, Y. Z. and Sun, H. M. and Jia, J. J.},
title = {{Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer's disease: a multi-omics Mendelian randomization study}},
journal = {Journal of translational medicine},
year = {2024},
doi = {10.1186/s12967-024-05680-z},
pmid = {39363202},
url = {https://doi.org/10.1186/s12967-024-05680-z}
}
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