Ongoing efforts to improve survival, and enhance quality of life have led biomedical research to focus on disease and the mechanisms that increase risk for disease. The other side of that coin may be as important, i.e. examining the protective factors that allow some individuals to enjoy long, healthy lives. One of the best examples of a gene that positively influences cognitive health is the apolipoprotein (APOE) e2 allele. The APOE e4 allele is a well-established risk factor for Alzheimer's disease (AD) and has thus dominated the APOE literature, with the putative protective role of e2 receiving little attention. This review describes the effects of APOE e2 on the structure and function of the brain. With a focus on neurodegeneration, we discuss evidence for APOE e2's protective effects, explore some key mechanisms through which this protection may be conferred, and address a few inconsistencies in the literature. Understanding the mechanisms that underlie the association between APOE e2, cognition and longevity may provide new targets for research on promoting life-long health. © 2013 Elsevier Ltd.