homo- and heterozygous alleles.141 The pathogenic nature of the E4 allele might be associated with the structural change of ApoE protein. ApoE protein has two major functional domains: a 22 kDa N-terminal and a 10 kDa C-terminal domain, connected by a hinge region. The E4 allele can promote domain interactions through the altered orientation of Arg61 in the N-terminal domain. Arg112 can interact with the Glu255 in the C-terminal domain, resulting in structural changes to ApoE protein, neuronal death, and neurodegeneration. Mouse experiments revealed that the mutation of Arg61 to Thr, or of Glu255 to Ala, may reduce the domain interactions.144–148 Figure 4 shows the differences between the E3 and E4 alleles.
