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, APOE*epsilon 4 increases, whereas APOE*epsilon 2 decreases the risk of late-onset AD compared with APOE*epsilon 3. Despite increased understanding of the detrimental effect of APOE*epsilon 4, it remains unclear how APOE*epsilon 2 confers protection against AD. Accumulating evidence suggests that APOE*epsilon 2 protects against AD through both amyloid-beta (A beta)-dependent and independent mechanisms. In addition, APOE*epsilon 2 has been identified as a longevity gene, suggesting a systemic effect of APOE*epsilon 2 on the aging process. However, APOE*epsilon 2 is not entirely benign; APOE*epsilon 2 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*epsilon 2 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.