First recognized as a major determinant in lipoprotein metabolism and 
cardiovascular disease, apolipoprotein (apo) E has emerged as an important 
molecule in several biological processes not directly related to its lipid 
transport function, including Alzheimer's disease and cognitive function, 
immunoregulation, and possibly even infectious diseases. ApoE is a polymorphic 
protein arising from three alleles at a single gene locus. The three major 
isoforms, apoE4, apoE3, and apoE2, differ from one another only by single amino 
acid substitutions, yet these changes have profound functional consequences at 
both the cellular and molecular levels. ApoE3 seems to be the normal isoform in 
all known functions, while apoE4 and apoE2 can each be dysfunctional. Isoform 
(allele)-specific effects include the association of apoE2 with the genetic 
disorder type III hyperlipoproteinemia and with both increased and decreased 
risk for atherosclerosis and the association of apoE4 with increased risk for 
both atherosclerosis and Alzheimer's disease, impaired cognitive function, and 
reduced neurite outgrowth; isoform-specific differences in cellular signaling 
events may also exist. Functional differences in the apoE isoforms that affect 
(or did affect) survival before the reproductive years probably account, at 
least in part, for the allele frequencies of the present day.