The accumulation of pathologic forms of tau is associated with neurodegeneration and cognitive decline in AD. New treatments that address this form of pathology could have direct therapeutic benefit for those with AD. We propose to test two novel compounds that target the DYRK1A protein, a kinase that we and others have implicated in the production of pathogenic forms of tau. Preliminary data indicates that these compounds reduce levels of phosphorylated tau protein in the brain and indicate that a comprehensive study examining the extent to which these compounds may delay the onset of AD-associated pathology and cognitive decline is warranted. This proposal seeks to conduct these studies using the well characterized 3X-TgAD mouse model for Alzheimer's disease. Successful completion of these studies is a necessary test of the hypothesis that therapeutics that reduce tau phosphorylation may have disease slowing or modifying effects and provide clinical benefit to those with AD.