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APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases
Shvetcov A, Johnson ECB, Winchester LM, Walker KA, Wilkins HM, Thompson TG, Rothstein JD, Krish V et al.. Nature medicine, 2025-07-15
Topic: Brain proteins, microglia and lab models
The APOE ε4 genetic variant is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is increasingly being implicated in other neurodegenerative diseases. Using the Global Neurodegeneration Proteomics Consortium SomaScan dataset covering 1,346 cerebrospinal fluid (CSF) and 9,924 plasma samples, we used machine learning-based proteome profiling to identify an APOE ε4 proteomic signature shared across individuals with AD, frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and nonimpaired controls. This signature was enriched in pro-inflammatory immune and infection pathways as well as immune cells, including monocytes, T cells and natural killer cells. Analysis of the dorsolateral prefrontal cortex proteome for 262 donors from the Accelerating Medicines Partnership for AD UPenn Proteomics Study revealed a consistent APOE ε4 phenotype, independent of neurodegenerative pathology, including amyloid-β tau and gliosis for all diseases, as well as TDP-43 in ALS and FTD cases, and α-synuclein in PD and PDD cases. While systemic proteomic changes were consistent across APOE ε4 carriers, their relationship with clinical and lifestyle factors, such as hypertension and smoking, varied by disease. These findings suggest APOE ε4 confers a systemic biological vulnerability that is necessary but not sufficient for neurodegeneration, emphasizing the need to consider gene-environment interactions. Overall, our study reveals a conserved APOE ε4-associated pro-inflammatory immune signature persistent across the brain, CSF and plasma irrespective of neurodegenerative disease, highlighting a fundamental, disease-independent biological vulnerability to neurodegeneration. This work reframes APOE ε4 as a pleiotropic immune modulator rather than an AD-specific risk gene, providing a foundation for precision biomarker development and early intervention strategies across neurodegenerative diseases.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Shvetcov, A., Johnson, E. C. B., Winchester, L. M., Walker, K. A., Wilkins, H. M., Thompson, T. G., et al. (2025). APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases. Nature medicine. https://doi.org/10.1038/s41591-025-03835-z
Vancouver
Shvetcov A, Johnson ECB, Winchester LM, Walker KA, Wilkins HM, Thompson TG, et al. APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases. Nature medicine. 2025. doi:10.1038/s41591-025-03835-z. PMID: 40665049.
BibTeX
@article{shvetcov2025-40665049,
author = {Shvetcov, A. and Johnson, E. C. B. and Winchester, L. M. and Walker, K. A. and Wilkins, H. M. and Thompson, T. G. and Rothstein, J. D. and Krish, V. and others},
title = {{APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases}},
journal = {Nature medicine},
year = {2025},
doi = {10.1038/s41591-025-03835-z},
pmid = {40665049},
url = {https://doi.org/10.1038/s41591-025-03835-z}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- Analysis of the dorsolateral prefrontal cortex proteome for 262 donors from the Accelerating Medicines Partnership for AD UPenn Proteomics Study revealed a consistent APOE ε4 phenotype, independent of neurodegenerative pathology, including amyloid-β tau and gliosis for all diseases, as well as TDP-43 in ALS and FTD cases, and α-synuclein in PD and PDD cases.
- These findings suggest APOE ε4 confers a systemic biological vulnerability that is necessary but not sufficient for neurodegeneration, emphasizing the need to consider gene-environment interactions.
- Overall, our study reveals a conserved APOE ε4-associated pro-inflammatory immune signature persistent across the brain, CSF and plasma irrespective of neurodegenerative disease, highlighting a fundamental, disease-independent biological vulnerability to neurodegeneration.
Why it matters
This study found that APOE ε4 carriers share immune-related proteomic changes across several neurodegenerative diseases, suggesting APOE ε4 confers a systemic biological vulnerability that is necessary but not sufficient for neurodegeneration. It is a biomarker and mechanism study and does not test any treatment, cure or prevention.
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Study details
- Evidence strengthLow
How this study scored 58/100
Published in a top-tier 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 | 10 / 10 | Tier 1 — top-tier general journal (Nature medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (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 | 4 / 7 | Cited 75 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 25.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 6 / 6 | Cited 40.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 3 / 4 | Cited 74 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Caitlin A. Finney: h-index 11 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Johns Hopkins University: institution h-index 2,306 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 11 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40665049) |
| Free to read | 2 / 2 | Free to read |
| Total | 58 / 100 | — |
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Read the original
- DOI: 10.1038/s41591-025-03835-z
- PubMed: 40665049
- Original source →
- Free full text: Nature Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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