Two polymorphic sites, located at codon 112 and 158, have been described in the human APOE gene. At least three main variations of the APOE gene have been identified, called “E2,” “E3,” and “E4” alleles. E3 was defined as a normal allele with Cys at codon 112 and Arg at codon 158. Two other APOE alleles have been described, the E2 and E4 alleles, which carry Arg158Cys and Cys112Arg polymorphisms, respectively.142,143 Six different genotypes can be distinguished with the following combinations: homozygous – E4/E4, E3/E3, and E2/E2 – and heterozygous – E2/E3, E2/E4, and E3/E4 (Table 2). E3 is the most common variant (77%), while E2 (8%) and E4 (15%) alleles have been detected less frequently. Higher frequencies of the E4 allele have been found among AD patients, and increased risk of AD can be found in patients with both 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
