Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression

Mutations in the presenilin 1 (PSEN1) gene have been implicated in 18-50% o f autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Als o, PSEN1 has been suggested as a potential risk gene in late-onset AD cases . We recently showed genetic association in a population-based study of EOA D, pointing to the 5' regulatory region of PSEN1, In this study we systemat ically screened 3.5 kb of the PSEN1 upstream region and found four novel po lymorphisms. Genetic analysis confirmed association of two polymorphisms wi th increased risk for EOAD. In addition, we detected two different mutation s in EOAD cases at -280 and -2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type -280 variant s using luciferase reporter gene expression in transiently transfected neur oblastoma cells showed a 30% decrease in transcriptional activity for the m utant -280G PSEN1 promoter variant compared with the wild-type variant -280 C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region reading to alte red expression levels of the PSEN1 protein.