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Cited by 44Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

A multi‐hit hypothesis for an APOE4 ‐dependent pathophysiological state

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Steele, Oliver George, Stuart, Alexander Cameron, Minkley, Lucy, Shaw, Kira, Bonnar, Orla, Anderle, Silvia, Penn, Andrew Charles, Rusted, Jennifer +3 more·2022·European Journal of Neuroscience
DOI 10.1111/ejn.15685PMC PMC9796338
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Abstract

The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late‐onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2 . Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease‐related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4 , given the low global prevalence of APOE2 . A multi‐hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi‐hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE ‐centric literature.

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  • A leaky BBB increases plasma proteins in the brain parenchyma, leading to oxidative stress and neuroinflammation, and is another mechanism by which APOE could prime the brain for neurodegeneration.

    “A leaky BBB increases plasma proteins in the brain parenchyma, thereby leading to oxidative stress and neuroinflammation, and is yet another mechanism by which APOE could prime the brain for neurodegeneration145.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [145]

    In ‘HIT 2: Neurovascular Dysfunction’ (page unavailable), Figure 2 says that APOE4-related BBB leakage increases blood-borne proteins in the CSF, increasing neuroinflammation and oxidative stress. The discussion links this inflammatory state to degenerative risk. The cited passage specifies CSF, however, not the brain parenchyma named in the claim. (LLM, conf=0.83)

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Authors
Steele, O. G., Stuart, A. C., Minkley, L., Shaw, K., Bonnar, O., Anderle, S., Penn, A. C., Rusted, J., Serpell, L., Hall, C., & King, S.
Affiliations
University of Sussex (GB)
Corresponding author
Steele, Oliver George
ORCID
Venue
European Journal of Neuroscience
Publisher
Wiley
Published
2022-06-06
Volume
56
Issue
9
Pages
5476-5515
ISSN
  • 0953-816X (ISSN-L)
  • 1460-9568
DOI
10.1111/ejn.15685
PMC
PMC9796338
OpenAlex
W4229011298
Cited by
44
References
59
Citations by year
2026: 10 · 2025: 12 · 2024: 14 · 2023: 6 · 2022: 2
FWCI
1.17
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Neuroscience (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion, cc-by-nc-nd)
  • Figshare (submittedVersion, cc-by-nc-nd)
Funders
Alzheimer's Society
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, APOE3, APOE2, genetic risk factors, neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking, lipid metabolism, calcium homeostasis, transcriptional regulation, preclinical models, cognitive impairment
MeSH terms
Alzheimer Disease, Apolipoproteins E, Humans, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2

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