(300 WORDS MAX) Alzheimer's disease (AD) is currently the third most costly disease in the US and may have the dubious honor of ranking first by the middle of the 21st century if advances in the development of disease-modifying therapies cannot be achieved. The goal of this application is to begin using a variety of novel chemical approaches that we hope will eventually lead to new disease-modifying drugs for AD. The major drug target of our studies is the protein, tau, which forms the "neurofibrillary tangles" that accumulate in AD brain. We will also investigate another class of target, the beta-amyloid peptides that form the "amyloid plaques" which also amass in the brains of AD patients. Two general strategies will be used. We will test rationally designed "duplex peptides" for their potential to prevent AD-like damage to nerve cells that will be grown in culture. In addition, we will use ultra-fast methods to screen billions of antibodies and small chemicals for individuals that bind very tightly to tau or beta-amyloid. The antibodies and small chemicals that are selected by this method will then be tested in cultured nerve cells as described for the duplex peptides. These collective experiments will hopefully yield antibodies and small chemicals that can be tested next for efficacy and toxicity in mice that have been genetically engineered to mimic human AD, but those experiments are beyond the scope of this ADDF grant.