Lack of evidence to support the association of polymorphisms within the alpha- and beta-secretase genes (ADAM10/BACE1) with Alzheimer's disease.

Cleavage of the amyloid precursor protein (APP) occurs through either an amyloidogenic or a non-amyloidogenic pathway. The first results in the generation of beta-amyloid (Aβ) and is initiated through cleavage by the beta-site amyloid beta A4 precursor protein-cleaving enzyme 1 (BACE1). The second precludes the formation of Aβ through cleavage by alpha-secretase, an enzyme's activity demonstrated in a disintegrin metalloproteinase, ADAM10. To assess the contribution of variants in the BACE1 and ADAM10 genes we used a detailed fine mapping approach. Genotyping of 11 single nucleotide polymorphisms covering the complete BACE1 gene, and 27 covering the entire ADAM10 gene, revealed no single-marker or haplotypic association with AD. We conclude that, in this present study, neither ADAM10 nor BACE1 present with any evidence to suggest that they are major candidate genes involved in conferring risk for AD.