AbstractInvestigations 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*ε4increases, whereasAPOE*ε2decreases the risk of late-onset AD compared withAPOE*ε3. Despite increased understanding of the detrimental effect ofAPOE*ε4, it remains unclear howAPOE*ε2confers protection against AD. Accumulating evidence suggests thatAPOE*ε2protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition,APOE*ε2has been identified as a longevity gene, suggesting a systemic effect ofAPOE*ε2on the aging process. However,APOE*ε2is not entirely benign;APOE*ε2carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect ofAPOE*ε2against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect ofAPOE2to treat AD.