Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

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Abstract

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.

Key points

  • The 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.

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Fig. 1: Structure of lipid-free and lipid-bound APOE3.
Fig. 2: Association of age with prevalence estimates of amyloid positivity according to cognitive status and apolipoprotein E (APOE) genotype.
Fig. 3: APOE isoforms and Aβ aggregation and clearance.
Fig. 4: Effects of APOE4 on AD pathogenesis pathways.
Fig. 5: Model of precision medicine based on APOE genotype.

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Acknowledgements

Support for work conducted in the authors’ laboratory was provided by the National Institutes of Health, the Cure Alzheimer’s Fund, the BrightFocus Foundation, the Alzheimer’s Association, the American Heart Association, the MetLife Foundation for Medical Awards Program and the Mayo Foundation for Medical Education and Research. The authors also thank C. Stetler for critical reading and editing of the manuscript.

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Correspondence to Guojun Bu.

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Yamazaki, Y., Zhao, N., Caulfield, T.R. et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15, 501–518 (2019) doi:10.1038/s41582-019-0228-7

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