The present invention is directed to isolated nucleic acids encoding Mint protein variants having enhanced abilities to modulate the transcriptional activation mediated by the cytoplasmic tail of the amyloid precursor protein (APP) relative to wild-type Mint proteins. The present invention is further directed toward purified Mint protein variants having enhanced abilities to modulate the transcriptional activation mediated by the cytoplasmic tail of APP relative to wild-type Mint proteins. The present invention also encompasses methods of modulating transcriptional activation and methods of identifying compounds that modulate transcriptional activation, and vectors, as well as transfected cells and kits useful for modulating transcriptional activation or for the identification of compounds that can modulate transcriptional activation. The present invention further encompasses transgenic knockout mice with little or no expression of Mint 1, Mint 2 or Mint 3 proteins. Such reagents may be useful as candidate therapeutics for Alzheimer's disease (AD), or as models for the rational design of drugs useful for the treatment of AD.