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 may have been overlooked. This is due, in large part, to a lack of recognition that the most common allele of the APOE gene, ε3, increases risk of AD relative to the ε2 allele. When the impact of both ε3 and ε4 alleles of APOE are considered, the majority of late-onset AD appears to be 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 might 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. Taken together, these lines of epidemiological evidence suggest that APOE is a predominant cause of AD, spanning the aetiologies of many forms of the disease. Consequently, almost all prospective cases of AD might benefit from the development of therapies to modulate APOE’s role in AD pathophysiology.