Program Director/Principal Investigator (Last, First, Middle): Miao-Kun Sun Project Summary/Abstract The importance of memory impairment and dementias, including Alzheimer’s disease (AD), as a global priority has been well recognized. Many compounds that target AD pathologies have been developed preclinically but have failed in clinical trials, mostly for the lack of therapeutic efficacies. Neurotrope Bioscience Inc. is developing bryostatin-1, a relatively selective protein kinase Cε activator, for the treatment of AD (IND 71,276). Bryostatin-1 has a combination of some unique pharmacological profiles, including enhancing activation of the brain-derived neurotrophic factor (BDNF) signaling pathways, pro-synaptic remodeling, pro-synaptogenesis, pro-synaptic maturation, anti-apoptosis, anti-Aβ oligomers, anti- hyperphosphorylated tau, and anti-inflammatory. Importantly, at appropriate doses, it has been found well tolerated in clinical trials and to produce a period of therapeutic efficacy for the treatment of the advanced AD patients in the absence of memantine. It is not clear, however, whether the therapeutic benefit would last, a profile highly desirable for AD, which lasts years and even decades. The objective of this proposal is to directly test the long-term therapeutic benefit of the chronic bryostatin-1 (synthetic) treatment for the advanced AD patients. The proposed study will establish whether a 12-week treatment with synthetic bryostatin-1, through restoring synaptic functions and enhancing synaptic capacity in supporting cognitive challenges in addition to actions of anti-AD pathologies, will effectively produce long-term and effective improvements in cognition of the advanced AD patients. If the therapeutic effect is short-lived, a second treatment will be applied to reverse the cognitive decline after the end of the first 12-week treatment. The clinical trial research is entirely for the development of innovative therapeutics that may advance progress in preventing and treating AD and other AD-related dementias, a necessary and important phase IIa trial for the commercial development of AD therapeutics. We anticipate that completion of this study would greatly facilitate progress in treating AD and other AD-related dementias and speed-up the commercialization of the effective therapeutics into market, thus paving the road toward successful outcomes in AD therapy. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page