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Cited by 91Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities

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Belaidi, Abdel Ali, Bush, Ashley I., Ayton, Scott·2025·Molecular Neurodegeneration
DOI 10.1186/s13024-025-00843-yPMC PMC12023563
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Abstract

Apolipoprotein E (APOE- gene; apoE- protein) is the strongest genetic modulator of late-onset Alzheimer’s disease (AD), with its three major isoforms conferring risk for disease ε2 < ε3 < ε4. Emerging protective gene variants, such as APOE Christchurch and the COLBOS variant of REELIN, an alternative target of certain apoE receptors, offer novel insights into resilience against AD. In recent years, the role of apoE has been shown to extend beyond its primary function in lipid transport, influencing multiple biological processes, including amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, autophagy, cerebrovascular integrity and protection from lipid peroxidation and the resulting ferroptotic cell death. While the detrimental influence of apoE ε4 on these and other processes has been well described, the molecular mechanisms underpinning this disadvantage require further enunciation, particularly to realize therapeutic opportunities related to apoE. This review explores the multifaceted roles of apoE in AD pathogenesis, emphasizing recent discoveries and translational approaches to target apoE-mediated pathways. These findings underscore the potential for apoE-based therapeutic strategies to prevent or mitigate AD in genetically at-risk populations.

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  • Genetic discoveries have identified AD susceptibility loci beyond APOE, involved in lipid metabolism, endosomal trafficking, and immune regulation.

    “Genetic discoveries have provided further depth, identifying susceptibility loci beyond apolipoprotein E (APOE), such as those involved in lipid metabolism, endosomal trafficking, and immune regulation [17].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [17]

    The Neuroinflammation section (page unavailable) says genetic studies identified TREM2 variants associated with increased AD risk, supporting a susceptibility locus beyond APOE involved in immune regulation. The section on apoE receptors also discusses a genetic association involving LRP1B, but only for age at AD onset in a familial cohort. The copy does not establish the claimed set of susceptibility loci spanning lipid metabolism and endosomal trafficking. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Belaidi, A. A., Bush, A. I., & Ayton, S.
Affiliations
The University of Melbourne (AU)
Corresponding author
Belaidi, Abdel Ali
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2025-04-24
Volume
20
Issue
1
Pages
47-47
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-025-00843-y
PMC
PMC12023563
OpenAlex
W4409755068
Cited by
91
References
70
Citations by year
2026: 60 · 2025: 31
FWCI
10.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • National Health and Medical Research Council (GNT1194028)
  • Alzheimer's Association (AARGD-24-1294531, ABA-25-1361586)
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
apolipoprotein E, Alzheimer's disease, APOE ε4, amyloid-beta aggregation, tau pathology, neuroinflammation, autophagy, cerebrovascular integrity, lipid peroxidation, ferroptosis, apoE receptors, genetic risk, therapeutic target
MeSH terms
Reelin Protein, Alzheimer Disease, Animals, Apolipoproteins E, Humans, Amyloid beta-Peptides

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