Alzheimer's disease (AD) is a devastating illness with enormous impact on patients, families, and the health care system. The proposed studies will investigate in animal models the safety and potential efficacy of a new treatment for AD. Our proposal is to develop small molecule drugs aimed at a novel target for the treatment of cognitive impairments of Alzheimer's disease and other dementias. Our approach will affect changes in brain function by modulating gene expression and protein levels through regulatory proteins, known as epigenetic mechanisms. No existing drugs for the treatment of cognitive impairment work through such epigenetic mechanisms. However, drugs for other diseases, including cancer, have been developed that work through epigenetic mechanisms. These cancer drugs are not specific enough to be used chronically, and have known safety concerns, as they broadly affect many aspects of the epigenetic system. We propose to discover highly specific drugs that will increase proteins involved in brain function while sparing the function of proteins critical for other biological processes. The studies in this proposal will demonstrate that the safety of these newly discovered compounds relative to older drugs, as well as demonstrate the ability of these compounds to increase brain proteins, improve brain function, and enhance cognition in animal models. With these data in hand, the compound can then move toward human clinical trials.