Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimerʹs disease

Alzheimerʹs disease (AD) is characterized by formation of plaques of amyloid β peptide (Aβ). Autosomally-inherited or “familial” AD had been demonstrated only in connection with coding sequence mutations. We characterized DNA–protein interaction and expression influence of two polymorphisms that occur in the promoter (C ↔ T at −3829 and T ↔ C at −1023, +1 transcription start site) of the Aβ precursor protein (APP) gene. We report distinct functional differences in reporter expression and in DNA–protein interaction for variant sequences in both −3829 and −1023 polymorphic regions. The −3829T variant has reduced DNA–protein interaction and reporter expression compared to −3829C, while −1023C has greater DNA–protein interaction and reporter expression than −1023T. Our predictions for likely transcription factors for loss of function (−3829T) are ADR1, MIG1, and PuF, and for gain of function (−1023C) are E12/E47, ITF-2, and RFX2. Characterization of the activity of a regulatory polymorphism of the APP gene points towards understanding mechanisms that likely underlie the majority of AD cases and may contribute to promoter-based drug design.