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APOE genotype regulates pathology and disease progression in synucleinopathy
Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, Haines JN, Dhavale DD et al.. Science translational medicine, 2020-02-01
Topic: Brain proteins, microglia and lab models
Apolipoprotein E ( APOE ) ε4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that APOE ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.
Key findings
- Apolipoprotein E ( APOE ) ε4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies.
- At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable.
- By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice.
- A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes.
- In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice.
Why it matters
In mouse models, the APOE e4 genotype was linked to greater accumulation of phosphorylated alpha-synuclein and more reactive gliosis, while APOE e2 mice showed increased survival and better motor performance. In two human Parkinson's disease cohorts, APOE e4/e4 individuals showed the fastest cognitive decline, but this is early research and does not establish a treatment for Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 51/100
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 (Science translational medicine) |
| Journal's citation record | 3 / 4 | Science Translational Medicine: journal h-index 365 (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 | 2 / 5 | 2020 — within 10 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 | 5 / 7 | Cited 174 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 21.8 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 4 / 6 | Cited 8.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 14 other studies in this library |
| Still being cited | 3 / 4 | Cited 78 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author David M. Holtzman: h-index 206 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 32024799) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 51 / 100 | — |
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Read the original
- DOI: 10.1126/scitranslmed.aay3069
- PubMed: 32024799
- Original source →
- Free full text: PubMed Central →
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
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APA 7th
Davis, A. A., Inman, C. E., Wargel, Z. M., Dube, U., Freeberg, B. M., Galluppi, A., et al. (2020). APOE genotype regulates pathology and disease progression in synucleinopathy. Science translational medicine. https://doi.org/10.1126/scitranslmed.aay3069
Vancouver
Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, et al. APOE genotype regulates pathology and disease progression in synucleinopathy. Science translational medicine. 2020. doi:10.1126/scitranslmed.aay3069. PMID: 32024799.
BibTeX
@article{davis2020-32024799,
author = {Davis, A. A. and Inman, C. E. and Wargel, Z. M. and Dube, U. and Freeberg, B. M. and Galluppi, A. and Haines, J. N. and Dhavale, D. D. and others},
title = {{APOE genotype regulates pathology and disease progression in synucleinopathy}},
journal = {Science translational medicine},
year = {2020},
doi = {10.1126/scitranslmed.aay3069},
pmid = {32024799},
url = {https://doi.org/10.1126/scitranslmed.aay3069}
}
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