Revised abstract Alzheimer Disease (AD) is a progressive brain disease that is the most common cause of senile dementia. More than 4.5 million Americans have been diagnosed with AD, and this number is expected to triple in the next 40-50 years. There is currently no cure for AD. The treatments available today for AD are symptomatic and do not interfere with inexorable progression of the underlying disease process. There is a desperate need for interventions that might improve symptoms and modify the disease progression. The two defining neuropathological features of AD are abnormal aggregation and deposition of ABeta peptides and tau in the brain as, respectively, extracellular neuritic plaques (NP) and intracellular neurofibrillary tangles (NFT). In the brain, monomeric ABeta peptides and tau proteins are aggregated to form high molecular weight, soluble multimeric neurotoxic ABeta and tau species. Continual progressive aggregations of multimeric ABeta and tau species result in deposition of ABeta and tau into, respectively, NP and NFT. Recent experimental evidence indicates that it is the accumulation of soluble high molecular weight (HMW) oligomeric ABeta and tau species in the brain, rather than deposition of NP and NFT per se, may be specifically related to cognitive dysfunction in AD. Pasinetti and colleagues recently demonstrated that a select grapeseed polyphenol extract (GSPE), namely, MegaNatural-Az GSPE to potently inhibit the aggregation of both ABeta peptides and tau proteins. Thus, MegaNatural-Az GSPE may benefit AD by mitigating both ABeta- and tau mediated neurotoxic responses. Based on this and evidence demonstrated the high tolerability and safety of long-term application of MegaNatural-Az in both laboratory animals and in human. The proposed study represents collaboration between basic science research laboratories and the Alzheimer?s Disease Clinical Core at the Mount Sinai School of Medicine to explore the development of MegaNatural-Az for treating AD. In particular, our proposed study will establish safety and pharmacokinetics of Meganatural-Az GSPE in AD subjects. As secondary measures, we will also evaluate clinical and biomarker indexes of therapeutic efficacy, including FDG PET* and hippocampal volumetry*. MRI* will also be used to survey for amyloid-related imaging abnormalities. The proposed study will provide the essential human data to guide the design of future studies to test the role of GSPE in mitigating cognitive decline in AD patients. (*=companion neuroimaging study supported by Constellation Wines, Inc.)