Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
By Yu Yamazaki, Na Zhao, Thomas R. Caulfield, Chia-Chen Liu, G. Bu. Nature Reviews Neurology, 2019
1,192 citations recorded by the source corpus.
Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.Polymorphism in the apolipoprotein E (APOE) gene influences the risk of Alzheimer disease (AD). The authors describe recent research into the role of APOE in AD pathogenesis and discuss how new AD therapies could be tailored to APOE genotype.Key pointsThe apolipoprotein E (APOE) gene has three major allelic variants, APOE*ε2, APOE*ε3 and APOE*ε4; APOE*ε4 is associated with an increased risk and lower age of onset of Alzheimer disease (AD), whereas APOE*ε2 seems to confer protection against AD.Increasing evidence suggests that the effect of APOE*ε4 on AD risk is exerted through inhibition of amyloid-β (Aβ) clearance and promotion of Aβ aggregation.APOE influences tau pathology and tau-mediated neurodegeneration in an isoform-dependent manner, although the relevance of this observation to AD pathogenesis requires further investigation.APOE4 contributes to AD pathogenesis by impairing microglial responsiveness, lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular integrity and function; some of these effects are independent of Aβ-related pathways.Current research into APOE-targeted AD therapeutic strategies aims to modulate APOE quantity and lipidation, APOE structural properties, APOE–Aβ interaction and APOE receptor expression.
Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology
View Paper: https://www.semanticscholar.org/paper/a47978eb270296d96a6a433309d575bbf4df4a7a
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In Physiology
Citations in the corpus
- Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “APOE also affects tau pathogenesis and tau-mediated neurodegeneration [468].”
- Role of neuroinflammation in neurodegeneration development (2023, background): “Compared with APOE3, the APOE4 isoform increases AD risk and theAPOE2 isoform reduces AD risk.(166) A single amino acid difference between APOE3 and APOE4 leads to the changing of protein conformation which affects the binding of APOE with its receptors, lipids, and Aβ.”