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Cited by 306Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

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Li, Zonghua, Shue, Francis, Zhao, Na, Shinohara, Mitsuru, Bu, Guojun·2020·Molecular Neurodegeneration
DOI 10.1186/s13024-020-00413-4PMC PMC7640652
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Abstract

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants,APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition,APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However,APOE*ε2 is not entirely benign;APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

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  • ApoE2's protective effects are mediated primarily through altered LDLR binding and amyloid-β clearance rather than altered self-association.

    “Similarly, ApoE2 did not differ from ApoE3 in this assay, consistent with the view that ApoE2's protective effects are mediated primarily through altered LDLR binding and amyloid-β clearance rather than altered self-association (41,42).”

    From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [42]

    The Biology of APOE section reports much weaker LDLR binding by APOE2 than by APOE3, and the pathological-evidence section reports that APOE2 tends to clear amyloid-β across the blood–brain barrier more efficiently. But the working model proposes hyperlipidation as a central protective mechanism; it does not establish LDLR binding and amyloid-β clearance as the primary mechanisms or compare them with APOE self-association. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The amino acid substitution R158C, which distinguishes ApoE2 from ApoE3 and ApoE4, disrupts LDLR interaction in the lipidated state.

    “The amino acid substitution R158C, which distinguishes ApoE2 from ApoE3 and ApoE4, disrupts LDLR interaction in the lipidated state19,21.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [21]

  • APOE2 affords protection against Alzheimer's disease.

    “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 APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [8]

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Metadata

Authors
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G.
Affiliations
  • Mayo Clinic in Florida (US)
  • National Center for Geriatrics and Gerontology (JP)
Corresponding author
  • Shinohara, Mitsuru
  • Bu, Guojun
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2020-11-04
Volume
15
Issue
1
Pages
63-63
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-020-00413-4
PMC
PMC7640652
OpenAlex
W3096808785
Cited by
306
References
104
Citations by year
2026: 47 · 2025: 84 · 2024: 56 · 2023: 43 · 2022: 45 · 2021: 31
FWCI
3.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cure Alzheimer's Fund
  • Alzheimer's Research Trust
  • Hori Sciences and Arts Foundation
  • National Center for Geriatrics and Gerontology
  • National Institutes of Health
  • National Institute on Aging (R01AG027924, RF1AG057181, RF1AG046205, P30AG062677)
Topics
  • 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
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, APOE ε2, Alzheimer's disease, APOE ε4, genetic risk factors, amyloid-beta, neuroprotection, longevity, aging, cerebrovascular disease, treatment options
MeSH terms
Alzheimer Disease, Animals, Humans, Apolipoprotein E2

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