Understanding apolipoprotein E as a predominant cause of Alzheimer's disease

Abstract

The full contribution of apolipoprotein E (APOE) to Alzheimer’s disease (AD) burden in populations has been overlooked. This is due, in large part, to a lack of recognition that the most common allele of the APOE gene, ε3, is a cause of many AD cases. When contributions of both ε3 and ε4 alleles are considered, the majority of late-onset AD is clearly attributable to differences in APOE function or expression in populations of European ancestry and in other ethnic groups for which we have reliable data. Moreover, most sporadic early-onset AD may not occur without the contributions of APOE ε3 and ε4, and the two alleles may be component causes of most forms of AD arising from highly penetrant genetic mutations and trisomy 21. Taking these lines of epidemiological evidence together, APOE should be considered a predominant cause of AD, spanning the aetiologies of many forms of the disease. Consequently, almost all prospective cases of AD could benefit from the development of therapies to modulate APOE’s role in AD pathophysiology.