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

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, APOEε4 increases, whereas APOEε2 decreases the risk of late-onset AD compared with APOEε3. Despite increased understanding of the detrimental effect of APOEε4, it remains unclear how APOEε2 confers protection against AD. Accumulating evidence suggests that APOEε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOEε2 has been identified as a longevity gene, suggesting a systemic effect of APOEε2 on the aging process. However, APOEε2 is not entirely benign; APOEε2 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.