(300 WORDS MAX) Alzheimer's disease (AD) is the main cause of aging-related dementia, and its prevalence is rising as the number of elderly in our population increase. The disease currently afflicts over 5 million Americans, a number that is predicted to triple by 2050. With the increasing longevity of many populations around the world, AD is a medical problem of mounting social and economic impact. The predicted increase in AD cases could make our health care system collapse. Thus, there is an urgent need to deepen our understanding of this most common of all neurodegenerative disorders and develop better strategies to prevent and reverse it, neither of which is currently possible. Abeta peptides are widely thought to cause AD, and many new AD treatments in clinical trials aim to lower the production of Abeta or increase its removal. However, the efficacy and long-term safety of these treatments are unknown. Therefore, it is important to search for alternative approaches to treat AD progression. Using mouse models of AD, we discovered that even a partial reduction of the protein tau can prevent Abeta from causing cognitive deficits and related neuronal abnormalities. Importantly, tau reduction had no significant side effects when implemented early during development, suggesting that drugs that either reduce tau levels or inhibit its actions could prevent AD or block its relentless progression. In this proposal, we will unravel the molecular pathways that regulate tau expression, with the ultimate goal of identifying drugs that can inhibit tau expression and prevent AD. We will screen a genome-wide RNAi library to identify modulators of tau transcription, translation and degradation. Some of these novel targets could be used in the future to identify drugs that can prevent the development and progression of AD by lowering neuronal tau levels or blocking the biological activities of this intriguing protein.