Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population

Presenilin-1 (PSEN-1) is a component of the gamma-secretase complex involved in beta-amyloid precursor protein (beta APP) processing. To date about 140 pathogenic mutations in the PSEN-1 gene have been identified and their main biochemical effect is to increase the production of the fibrillogenic peptide A beta(1-42). An exception is the PSEN-1 [E318G] mutation that does not alter A beta(1-42) generation and is generally considered a non-pathogenic polymorphism. Nevertheless, this mutation was reported to be a genetic risk factor for familial Alzheimer's disease (FAD) in the Australian population. To independently confirm this indication, we performed a case-control association study in the Italian population. We found a significant association (p < 0.05, Fisher's exact test) between the presence of PSEN-1 [E318G] and FAD. In addition, on measuring the A beta(1-42) and A beta(1-40) concentrations in fibroblast-conditioned media cultured from PSEN-1 [E318G] carriers and PSEN-1 [wild type] controls we noted a significant decrease (p < 0.05, Mann-Whitney test) in the A beta(1-42)/A beta(1-40) ratio in PSEN-1 [E318G] carriers, suggesting a peculiar biochemical effect of this mutation. (c) 2006 Elsevier Inc. All rights reserved.