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Genome‐wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease
Xu Hou, Michael G. Heckman, Fabienne C. Fiesel, Shunsuke Koga, Alexandra I. Soto‐Beasley, Jens O. Watzlawik, Jing Zhao, Rebecca R. Valentino et al.. Alzheimer s & Dementia, 2025-04-01
Topic: Brain proteins, microglia and lab models
We identified a significant genome-wide association with p-S65-Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p-S65-Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4-mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p-S65-Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role. Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience. HIGHLIGHTS: p-S65-Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p-S65-Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology-dependent and pathology-independent mechanisms. ZMIZ1 was linked to reduced p-S65-Ub and neuropathology indicative of protection.
Key findings
- We identified a significant genome-wide association with p-S65-Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1).
- APOE4 was associated with higher p-S65-Ub levels and greater neuropathological burden.
- Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4-mediated mitophagy alterations.
- Intriguingly, ZMIZ1 rs6480922 was associated with lower p-S65-Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.
- Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.
Why it matters
A genome-wide association analysis found that the APOE4 variant was linked to higher levels of a marker of mitochondrial damage and greater neuropathological burden in Lewy body disease, with functional validation in mouse and human cell models. The findings concern disease risk and resilience mechanisms and do not test any treatment, cure or prevention for Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (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 | 2025 — 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 9 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 5.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 9 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Wolfdieter Springer: h-index 38 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40309932) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Hou, X., Heckman, M. G., Fiesel, F. C., Koga, S., Soto‐Beasley, A. I., Watzlawik, J. O., et al. (2025). Genome‐wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease. Alzheimer s & Dementia. https://doi.org/10.1002/alz.70198
Vancouver
Hou X, Heckman MG, Fiesel FC, Koga S, Soto‐Beasley AI, Watzlawik JO, et al. Genome‐wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease. Alzheimer s & Dementia. 2025. doi:10.1002/alz.70198. PMID: 40309932.
BibTeX
@article{hou2025-40309932,
author = {Hou, Xu and Heckman, Michael G. and Fiesel, Fabienne C. and Koga, Shunsuke and Soto‐Beasley, Alexandra I. and Watzlawik, Jens O. and Zhao, Jing and Valentino, Rebecca R. and others},
title = {{Genome‐wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz.70198},
pmid = {40309932},
url = {https://doi.org/10.1002/alz.70198}
}
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