Interaction between the APOE var epsilon4 allele and the APH-1b c + 651T > G SNP in Alzheimerʹs disease

The γ-secretase complex is a multimeric aspartyl protease which plays a pivotal role in the production of amyloid β-peptide, the main component of senile plaques in Alzheimerʹs disease (AD). APH-1a and APH-1b have been recently identified as important subunits of the γ-secretase complex. We previously studied sequence variations in both genes and their association with AD in a small Italian population. The rare polymorphism c + 651T > G in APH-1b showed a possible interaction with the Apolipoprotein E (APOE) var epsilon4 allele in the AD population sample. We extended our genetic analysis to 449 AD patients and 435 controls and, in AD cases, we found a significant interaction (P = 0.001) between the allelic variants in the two genes, resulting in a marked increase of the relative risk for AD (OR = 28.6). Despite the amino acid substitution does not seem to modify either the intracellular localization or the half-life of APH-1b protein, these data suggest that a cooperative mechanism involving APOE and APH-1b plays a role in the susceptibility to develop AD.