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APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology
Open accessAbstract
Objective To evaluate whether APOE ε4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology. Methods Six hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for APOE. In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between APOE ε4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with ε4 according to severity of AD pathology. Results As expected, APOE ε4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios ≥3.42, all p ≤ 0.004). Of note, ε4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, p = 0.001). In the low AD pathology LBD subgroup, ε4 was associated with significantly more LB counts in the 5 cortical regions, independently of Braak stage and Thal phase (all p ≤ 0.002). Conclusions Our results indicate that APOE ε4 is independently associated with a greater severity of LB pathology. These findings increase our understanding of the mechanism behind reported associations of ε4 with risk of dementia with Lewy bodies and Parkinson disease with dementia, and suggest that ε4 may function as a modifier of processes that favor LB spread rather than acting directly to initiate LB pathology.
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“APOEε4 has also been associated with the burden of α-synuclein inclusions in LBD with minimal AD co-pathology62,71, although other studies have only found an association between APOEε4 and LBD in the presence of AD neuropathology, but not in pure LBD72,73.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [62]
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“Specifically, APOEε4 carriage has been independently associated with increased odds and severity of Lewy body pathology49,62 and TDP-43 pathology59,63,64 and with the presence of TDP-43-related hippocampal sclerosis63 in the scenario of a primary neuropathological diagnosis of AD.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [62]
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Metadata
- Authors
- Dickson, D. W., Heckman, M. G., Murray, M. E., Soto, A. I., Walton, R. L., Diehl, N. N., van Gerpen, J. A., Uitti, R. J., Wszolek, Z. K., Ertekin-Taner, N., Knopman, D. S., Petersen, R. C., Graff-Radford, N. R., Boeve, B. F., Bu, G., Ferman, T. J., & Ross, O. A.
- Affiliations
- Mayo Clinic (US)
- From the Department of Neuroscience (D.W.D., M.E.M., A.I.S., R.W., N.E.-T., G.B., O.A.R.), Division of Biomedical Statistics and Informatics (M.G.H., N.N.D.), and Departments of Neurology (J.A.v.G., R.J.U., Z.K.W., N.E.-T., N.R.G.-R.) and Psychiatry and Psychology (T.J.F.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (D.S.K., R.C.P., B.F.B.), Mayo Clinic, Rochester, MN.
- ORCID
- Venue
- Neurology
- Published
- 2018-09-18
- Volume
- 91
- Issue
- 12
- Pages
- e1182-e1195
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC6161556
- OpenAlex
- W2888557643
- Cited by
- 210
- References
- 5
- Citations by year
- 2026: 18 · 2025: 39 · 2024: 28 · 2023: 20 · 2022: 30 · 2021: 27 · 2020: 26 · 2019: 21 · 2018: 1
- FWCI
- 12.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (R01AG015866, RF1AG051504, R01AG027924, U01AG045390, RF1AG046205, U01AG046139, R01AG046205, R01AG061796, R01AG035355, P50AG016574)
- National Institute of Neurological Disorders and Stroke (R01NS080820, R01NS078086, U54NS100693, P50NS072187, P01NS074969)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, Lewy body pathology, Alzheimer disease pathology, dementia with Lewy bodies, Parkinson's disease dementia, genetic risk, Braak stages, cortical Lewy bodies
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genotype, Humans, Male, Case-Control Studies, Lewy Body Disease
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- CoChat. (2026). Citation check: APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. https://app.cochat.ai/papers/10.1212/wnl.0000000000006212
- The paper
- Dickson, D. W., Heckman, M. G., Murray, M. E., Soto, A. I., Walton, R. L., Diehl, N. N., van Gerpen, J. A., Uitti, R. J., Wszolek, Z. K., Ertekin-Taner, N., Knopman, D. S., Petersen, R. C., Graff-Radford, N. R., Boeve, B. F., Bu, G., Ferman, T. J., & Ross, O. A. (2018). APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology. https://doi.org/10.1212/wnl.0000000000006212
