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Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

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Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that causes progressive cognitive decline. The majority of AD cases are sporadic and late-onset (>65 years old) making it the leading cause of dementia in the elderly. While both genetic and environmental factors contribute to the development of late-onset AD (LOAD), APOE polymorphism is a major genetic risk determinant for LOAD. In humans, the APOE gene has three major allelic variants: ε2, ε3, and ε4, of which APOE ε4 is the strongest genetic risk factor for LOAD, whereas APOE ε2 is protective. Mounting evidence suggests that APOE ε4 contributes to AD pathogenesis through multiple pathways including facilitated amyloid-β deposition, increased tangle formation, synaptic dysfunction, exacerbated neuroinflammation, and cerebrovascular defects. Since APOE modulates multiple biological processes through its corresponding protein apolipoprotein E (apoE), APOE gene and apoE properties have been a promising target for therapy and drug development against AD. In this review, we summarize the current evidence regarding how the APOE ε4 allele contributes to the pathogenesis of AD and how relevant therapeutic approaches can be developed to target apoE-mediated pathways in AD.

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Fig. 1

The figure is updated and modified with permission from Karch and Goate [12]

Fig. 2
Fig. 3

The figure was adapted and reformatted with permission from Raichlen and Alexander [196]

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Yu Yamazaki, Meghan M. Painter, Guojun Bu & Takahisa Kanekiyo

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  1. Yu Yamazaki
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  2. Meghan M. Painter
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  3. Guojun Bu
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  4. Takahisa Kanekiyo
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Correspondence to Takahisa Kanekiyo.

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Funding

This work was supported by Grants from the National Institutes of Health (NIH) (P50AG016574, RF1AG051504, R01AG027924, R01AG035355, R01AG046205, and P01NS074969 to G.B.); American Heart Association (to T.K.); Japan Society for the Promotion of Science (JSPS) and Mochida Memorial Foundation for Medical & Pharmaceutical Research (to Y.Y.).

Conflict of interest

Yu Yamazaki, Meghan M. Painter, Guojun Bu and Takahisa Kanekiyo declare that they have no conflict of interest in relation to this work.

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Yamazaki, Y., Painter, M.M., Bu, G. et al. Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence. CNS Drugs 30, 773–789 (2016). https://doi.org/10.1007/s40263-016-0361-4

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