APOE2: protective mechanism and therapeutic implications for Alzheimer's disease.

Zonghua Li, Francis Shue, Na Zhao, Mitsuru Shinohara, Guojun Bu

Molecular neurodegeneration 2020 Nov 04

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Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer's disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

Citation

Zonghua Li, Francis Shue, Na Zhao, Mitsuru Shinohara, Guojun Bu. APOE2: protective mechanism and therapeutic implications for Alzheimer's disease. Molecular neurodegeneration. 2020 Nov 04;15(1):63