APOE ε4 increases risk for dementia in pure synucleinopathies
Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB et al.. JAMA neurology, 2013-02-01
Topic: Brain proteins, microglia and lab models
Objective To test for an association between the apolipoprotein E (APOE) ϵ4 allele and dementias with synucleinopathy. Design Genetic case-control association study. Setting Academic research. Patients Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). MAIN OUTCOME MEASURE The APOE allele frequencies. RESULTS The APOE ϵ4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ(2)(4)=185.25; P=5.56 × 10(-39)), and it was higher in the pDLB group than the PDD group (P= .01). In an age-adjusted and sex-adjusted dominant model, ϵ4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). CONCLUSIONS The APOE ϵ4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ϵ4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ϵ4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
Key findings
- RESULTS The APOE ϵ4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ(2)(4)=185.25; P=5.56 × 10(-39)), and it was higher in the pDLB group than the PDD group (P= .01).
- In an age-adjusted and sex-adjusted dominant model, ϵ4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6).
- This suggests that ϵ4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy.
- The elevated ϵ4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
Why it matters
In 909 autopsied brains, the APOE ε4 gene variant was more common in every dementia group than in controls (7.2% of gene copies), including dementia with Lewy bodies and Parkinson disease dementia in people whose brains showed little or no Alzheimer-type change (31.9% and 19.1%). After adjusting for age and sex, carrying ε4 was linked to about 6 times higher odds of "pure" Lewy body dementia and about 3 times higher odds of Parkinson disease dementia. The authors say this "suggests that ϵ4 increases the likelihood of presenting with dementia" in these diseases, possibly through routes "unrelated to amyloid processing", but this is an association, not proof of cause.
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Study details
- Study designcase-control study
- Participants244
- Effect size38.1%; 40.6%; 31.9%
- Evidence strengthModerate
How this study scored 69/100
Published in a leading specialty journal, and it is a case-control study. Scored zero for randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (JAMA neurology) |
| Journal's citation record | 2 / 4 | JAMA Neurology: journal h-index 235 (OpenAlex, 2026-10-29) |
| Study design | 6 / 12 | A case-control study |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2013 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 244 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 6 / 7 | Cited 386 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 25.7 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 4 / 6 | Cited 9.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 40 other studies in this library |
| Still being cited | 3 / 4 | Cited 93 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Cyrus P. Zabetian: h-index 72 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23407718) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 69 / 100 | — |
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Read the original
- DOI: 10.1001/jamaneurol.2013.600
- PubMed: 23407718
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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. 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.
APA 7th
Tsuang, D., Leverenz, J. B., Lopez, O. L., Hamilton, R. L., Bennett, D. A., Schneider, J. A., et al. (2013). APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA neurology. https://doi.org/10.1001/jamaneurol.2013.600
Vancouver
Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, et al. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA neurology. 2013. doi:10.1001/jamaneurol.2013.600. PMID: 23407718.
BibTeX
@article{tsuang2013-23407718,
author = {Tsuang, D. and Leverenz, J. B. and Lopez, O. L. and Hamilton, R. L. and Bennett, D. A. and Schneider, J. A. and Buchman, A. S. and Larson, E. B. and others},
title = {{APOE ε4 increases risk for dementia in pure synucleinopathies}},
journal = {JAMA neurology},
year = {2013},
doi = {10.1001/jamaneurol.2013.600},
pmid = {23407718},
url = {https://doi.org/10.1001/jamaneurol.2013.600}
}
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