Eur J of Neuroscience - 2022 - Steele - A multi%E2%80%90hit hypothesis for an APOE4%E2%80%90dependent pathophysiological state.pdf (26.72 MB)
A multi-hit hypothesis for an APOE4-dependent pathophysiological state
journal contribution
posted on 2023-06-15, 20:39 authored by Oliver SteeleOliver Steele, Alex StuartAlex Stuart, Lucy Minkley, Kira ShawKira Shaw, Orla Bonnar, Silvia Anderle, Andrew PennAndrew Penn, Jennifer Rusted, Louise SerpellLouise Serpell, Catherine HallCatherine Hall, Sarah KingSarah KingThe 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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- Published
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- Published version
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Eur J NeurosciISSN
0953-816XPublisher
WileyExternal DOI
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FranceDepartment affiliated with
- Neuroscience Publications
Full text available
- Yes
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- Yes
Legacy Posted Date
2022-06-14First Open Access (FOA) Date
2022-06-14First Compliant Deposit (FCD) Date
2022-06-13Usage metrics
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