 The goal of this proposal is to show that, nicotinamide NA, a B3 vitamin, is safe and effective for the treatment of patients with mild to moderate Alzheimers disease AD. NA is known to block the ability of certain proteins to regulate other proteins by removing their acetyl groups. Recent evidence has demonstrated that inhibitors such as NA prevent nerve cell degeneration in models of Huntingtons disease HD, Parkinsons disease and Lou Gehrigs disease or ALS. Despite these beneficial effects in many different animal models, there have been no studies to date using these inhibitors in AD. In some of our recent studies we found that the potent inhibitor, NA, significantly improves learning and memory in transgenic mice that develop AD. NA treatment also resulted in striking changes in tau, a protein that abnormally accumulates in AD. NA has been extensively used in clinical studies over the last 40 years and is generally safe and well-tolerated. As NA is a safe and readily available vitamin supplement, our recent results provide a strong argument for a study of NA in patients with AD. We therefore propose to treat 50 patients with mild to moderate AD with either NA 1500 milligrams twice a day or an identical but inactive drug placebo for 24 weeks. At 6 week intervals we will assess functions such as learning and memory, and ability to carry out daily activities as well as caregiver reports using standardized tests. We will also perform spinal taps at the beginning and end of the study to measure the level of abnormal tau protein in the cerebrospinal fluid. Blood tests will periodically be done to assess liver function and complete blood counts. The results of this study may provide the basis for a more extensive study of NA for the treatment of mild to moderate AD. 