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Cited by 378Dementia and Cognitive Impairment ResearchParkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatments

APOE ϵ4 Increases Risk for Dementia in Pure Synucleinopathies

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Tsuang, Debby, Leverenz, James B., Lopez, Oscar L., Hamilton, Ronald L., Bennett, David A., Schneider, Julie A., Buchman, Aron S., Larson, Eric B. +25 more·2013·JAMA Neurology
DOI 10.1001/jamaneurol.2013.600PMC PMC3580799
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Abstract

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.

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  • The ε4 allele of APOE is the major genetic risk factor for Alzheimer's disease and dementia with Lewy bodies.

    “The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for AD and dementia with Lewy bodies (DLB) (1, 5, 6), whereas APOE2, a well-established longevity determinant, affords protection against the disease (7, 8).”

    From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [6]

    The Abstract Results report strong associations of APOE ε4 with Alzheimer’s disease and pure dementia with Lewy bodies, and the Conclusions call it a strong risk factor across the Lewy body disease spectrum. The paper does not establish that it is *the major* genetic risk factor for either disease relative to other genetic factors. (LLM, conf=0.83)

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  • Recent genetic studies demonstrated a robust association between the APOE4 allele and risk of dementia with Lewy bodies.

    “Additionally, recent genetic studies have also demonstrated a robust association between the APOE4 allele and risk of DLB (6, 12), the second leading cause of dementia in the elderly.”

    From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [6]

  • The APOEε4 allele has been associated with increased risk of a dementia presentation in people with pure α-synucleinopathies.

    “Furthermore, the ε4 allele has been associated with increased risk of a dementia presentation in people with pure α-synucleinopathies70.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [70]

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Research works printed but not linked: 27

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Authors
Tsuang, D., Leverenz, J. B., Lopez, O. L., Hamilton, R. L., Bennett, D. A., Schneider, J. A., Buchman, A. S., Larson, E. B., Crane, P. K., Kaye, J. A., Kramer, P., Woltjer, R., Trojanowski, J. Q., Weintraub, D., Chen-Plotkin, A. S., Irwin, D. J., Rick, J., Schellenberg, G. D., Watson, G. S., Kukull, W., Nelson, P. T., Jicha, G. A., Neltner, J. H., Galasko, D., Masliah, E., Quinn, J. F., Chung, K. A., Yearout, D., Mata, I. F., Wan, J. Y., Edwards, K. L., Montine, T. J., & Zabetian, C. P.
Affiliations
  • University of Washington (US)
  • Group Health Cooperative (US)
Corresponding author
Zabetian, Cyrus P.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2013-02-01
Volume
70
Issue
2
Pages
223
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2013.600
PMC
PMC3580799
OpenAlex
W2012611625
Cited by
378
References
9
Citations by year
2026: 23 · 2025: 38 · 2024: 30 · 2023: 20 · 2022: 29 · 2021: 39 · 2020: 39 · 2019: 32 · 2018: 29 · 2017: 29 · 2016: 24 · 2015: 17 · 2014: 18 · 2013: 11
FWCI
9.96
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000531)
  • National Institute on Aging (R01AG010845, P30AG028383, R37AG018440, P50AG005133, U01AG006781, U01AG016976, P50AG005131, P30AG010124, R01AG015819, P30AG008017, P30AG010161, P01AG022074, P50AG005136, T32AG000255)
  • National Cancer Institute (R01CA149051)
  • National Institute of Neurological Disorders and Stroke (P50NS062684, R01NS065070, P50NS053488, R01NS048595)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
apolipoprotein E, dementia, synucleinopathies, Parkinson's disease dementia, Alzheimer's disease, Lewy body disease, genetic risk factors, neuropathology, genetic association, age and sex adjustment, Lewy bodies, neurofibrillary tangles
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Dementia, Female, Gene Frequency, Humans, Longitudinal Studies, Male, Middle Aged, Parkinson Disease, Retrospective Studies, Risk Factors, Up-Regulation, Case-Control Studies, Lewy Body Disease, Synucleins, Apolipoprotein E4

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