The forgotten APOE allele: A review of the evidence and suggested mechanisms for the protective effect of APOE ε2

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) epsilon 2 allele. The APOE epsilon 4 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 epsilon 2 receiving little attention. This review describes the effects of APOE epsilon 2 on the structure and function of the brain. With a focus on neurodegeneration, we discuss evidence for APOE epsilon 2'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 epsilon 2, cognition and longevity may provide new targets for research on promoting life-long health. (C) 2013 Elsevier Ltd. All rights reserved.