The incidence of Alzheimer's disease is expected to increase by nearly one million people per year to reach a total prevalence of about 16 million in America by the year 2050. The Alzheimer's association reports that Alzheimer's disease (AD) is the 6th leading cause of death in the United States of America and that it is the only Top-10 cause of death that currently has no prevention or effective treatment. Currently approved treatments for AD are not highly efficacious and are palliative at best. These drugs address symptoms but not the root/cause of the disease. Since the postulation of the "amyloid cascade hypothesis" that states that the beta-amyloid peptide was at the origin of the disease, most scientist and major pharmaceutical companies have focused their therapeutic approaches on targeting ways to reduce beta-amyloid peptide production or accumulation either by immunotherapy or by directly inhibiting the enzymes responsible for its production, beta- and/or gamma-secretase. However, over the years since AD was first described, it has become clear that several genes are linked to AD onset as well as to neuroprotection against AD. We thus decided to investigate small molecules that are able to affect several high-priority AD genes. We identified molecules that reduce a number of key players in AD progression such as beta amyloid protein, as well as BACE1 and tau gene expression; while increasing the expression of a number of neuro-protective genes: BDNF, alpha-secretase (ADAM10), Mint2, Fe65 and REST. We have shown that one of these molecules CTI-309 also restores memory in AD animal models, have honed in on its epigenetic mechanism and generated selective compounds. Funds from this grant will be used to investigate if this mechanism replicates results from CTI-309 and will be used to synthesize potential clinical candidates through medicinal chemistry efforts.