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Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18–50% of autosomal dominant cases with early-onset Alzheimer’s disease (EOAD). Also,  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 EOAD, pointing to the 5′ regulatory region of  PSEN1 . In this study we systematically screened 3.5 kb of the  PSEN1  upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations 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 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant    –   280G  PSEN1  promoter variant compared with the wild-type variant  – 280C. Our data suggest that the increased risk for EOAD associated with  PSEN1  may result from genetic variations in the regulatory region leading to altered expression levels of the  PSEN1  protein.

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