Association study between Alzheimer's disease and genes involved in Aβ biosynthesis, aggregation and degradation:: suggestive results with BACE1

Background Amyloid beta-peptide (Abeta) biosynthesis, aggregation and degradation constitute three important steps to consider in the study of pathological mechanisms involved in Alzheimer's disease (AD). Several proteins have been suggested as involved in each of these processes: proteolytic cleavage of the amyloid precursors protein by the beta-site APP cleaving enzyme (BACE), increased amyloid fibril formation by the activity of the acetylcholinesterase (ACHE gene), and degradation of Abeta aggregates by the plasmin system have been exhaustively documented. Methods A case-control design was used to evaluate the possible association between candidate genes involved in these three processes and AD. We analysed three polymorphisms located at the BACE1 gene, one polymorphism at the ACHE gene, and two variants located at the tissue plasminogen activator and plasminogen activator inhibitor-1 (genes TPA and PAI-1. respectively), both part of the plasmin system. Results We found an association between BACE1 exon 5 GG genotype and AD (age- and gender-adjusted odds ratio = 2.14, P = 0.014). Although a similar association was reported previously by Nowotny and collaborators only in subjects carrying the epsilon4-allele of the apolipoprotein E gene (APOE), we did not detect this effect. However, when we combined our results with those previously reported, a clear increase of the risk to develop AD appeared in subjects carrying both the BACE1 exon 5 GG genotype and the APOE epsilon4-allele (crude OR = 2.2, P = 0.004). Conclusion These data suggest a possible genetic relation between BACE1 and AD.