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Cited by 449Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

ApoE4: an emerging therapeutic target for Alzheimer’s disease

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Safieh, Mirna, Korczyn, Amos D., Michaelson, Daniel M.·2019·BMC Medicine
DOI 10.1186/s12916-019-1299-4PMC PMC6425600
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Abstract

BACKGROUND: The growing body of evidence indicating the heterogeneity of Alzheimer's disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that the development of a single magic cure suitable for all cases may not be possible. This calls for a shift in paradigm where targeted treatment is developed for specific AD subpopulations that share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of AD, is expressed in more than half of AD patients and is thus an important possible AD therapeutic target. REVIEW: This review focuses initially on the pathological effects of apoE4 in AD, as well as on the corresponding cellular and animal models and the suggested cellular and molecular mechanisms which mediate them. The second part of the review focuses on recent apoE4-targeted (from the APOE gene to the apoE protein and its interactors) therapeutic approaches that have been developed in animal models and are ready to be translated to human. Further, the issue of whether the pathological effects of apoE4 are due to loss of protective function or due to gain of toxic function is discussed herein. It is possible that both mechanisms coexist, with certain constituents of the apoE4 molecule and/or its downstream signaling mediating a toxic effect, while others are associated with a loss of protective function. CONCLUSION: ApoE4 is a promising AD therapeutic target that remains understudied. Recent studies are now paving the way for effective apoE4-directed AD treatment approaches.

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  • Across ApoE4-affected neurological diseases, lipid dyshomeostasis is consistently manifested.

    “Across ApoE4-affected neurological diseases, lipid dyshomeostasis is consistently manifested (Safieh et al., 2019).”

    From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Safieh et al., 2019

    The review’s “Lipid metabolism” section reports altered DHA levels and phospholipid and cholesterol dysregulation associated with apoE4 in the context of Alzheimer’s disease (page unavailable). Its “Impact of the APOE genotype on other diseases” section discusses DLB and tauopathy but does not establish that lipid dyshomeostasis consistently occurs across those diseases. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • ApoE4 is less prone to lipidation by ABCA1, being in a hypolipidated state that is thought to impair lipid metabolism, dysregulate cerebral cholesterol and phospholipids, and compromise synaptic integrity.

    “ApoE4 is less prone to lipidation by ABCA1, as previously mentioned, being in a hypolipidated state that is thought to impair lipid metabolism, dysregulate the levels of cerebral cholesterol and phospholipids and compromise synaptic integrity [45].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [45]

    The Lipid metabolism section (page unavailable) reports that apoE4 is hypolipidated and associates apoE4 with cholesterol and phospholipid dysregulation. The Approaches directed at the apoE4 protein section says apoE4 appears to be lipidated less effectively by ABCA1 and that increasing ABCA1 activity reverses synaptic impairments in mice. It does not establish that hypolipidation itself causes the cholesterol and phospholipid dysregulation; the review says the relevant lipid composition and mechanism remain uncertain. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Genome editing has not yet revealed effective results in animal models.

    “Despite its promising results in vitro, genome editing has not yet revealed effective results in animal models [45] and its translation to clinics might be challenging.”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [45]

    The “Gene editing of APOE4 by CRISPR” section reports successful cell-culture editing but says successful in vivo application to apoE4 mice had not yet been reported. This supports the claim for APOE4-targeted CRISPR, not its unqualified wording about genome editing in animal models generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D and HtrA1 are proteases able to cleave ApoE4 into neurotoxic fragments.

    “Nevertheless, as previously mentioned in this review, some authors identified collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D and HtrA1 as some of the proteases that are able to cleave ApoE4 into neurotoxic fragments.”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [45]

    The “ApoE degradation” section (page unavailable) says that distinct proteases can generate neurotoxic ApoE4 fragments. It does not identify collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D, or HtrA1 as those proteases. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Safieh, M., Korczyn, A. D., & Michaelson, D. M.
Affiliations
Tel Aviv University (IL)
Corresponding author
Michaelson, Daniel M.
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-03-20
Volume
17
Issue
1
Pages
64-64
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-019-1299-4
PMC
PMC6425600
OpenAlex
W2944325086
Cited by
449
References
45
Citations by year
2026: 29 · 2025: 60 · 2024: 63 · 2023: 57 · 2022: 73 · 2021: 88 · 2020: 65 · 2019: 14
FWCI
7.03
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Israel Science Foundation
  • Joseph Sagol Foundation
  • Harold Eleanore Foonberg Foundation
  • Joseph K. and Inez Eichenbaum Foundation
Topics
  • Health Sciences › Medicine › Physiology › 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
APOE ε4, Alzheimer's disease, therapeutic target, APOE gene, gain of toxic function, animal models of Alzheimer's disease, genetic risk factors, disease heterogeneity
MeSH terms
Alzheimer Disease, Animals, Humans, Mice, Apolipoprotein E4

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