Alzheimer's disease (AD) is an irreversible neurodegenerative disease that affects more than 5 million people in the United States. At the heart of this disease is progressive memory loss (cognitive decline and dementia). Currently, the few agents that are FDA-approved for treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Work from our laboratory over a number of years has shown that brain blood vessels in AD are abnormal. Indeed, increasing evidence suggests an important role for vascular (blood vessel) factors in the development of AD. We were the first laboratory to document that blood vessels from AD brains release proteins that can injure or kill brain nerve cells. The hypothesis to be tested in this grant is that blocking release of these proteins ("angiogenic proteins") will improve and/or prevent memory decline in an animal model of AD. We have exciting preliminary data that support this hypothesis. The process of discovering and developing drugs is lengthy and expensive. Thus, innovative, off-label use of FDA-approved drugs as novel treatments for AD is a timely and cost-effective strategy. To this end, we propose a new therapeutic strategy for AD that uses drugs that have already been developed and are in use for cancer therapy. These drugs may be able to prevent the release of "angiogenic proteins" from brain blood vessels in AD. Demonstration that these drugs are well-tolerated by AD mice and that administration of these drugs slows, halts or reverses memory loss in animal models of AD will provide the necessary rationale to fast-track this novel therapeutic approach into human clinical trials.