Posiphen lowers amyloid precursor protein and amyloid β as well as acetylcholinesterase levels in culture, animals and humans

Background: Major hallmarks of Alzheimer's disease (AD) are synaptic loss and abnormal protein deposition, particularly of toxic amyloid-β (Aβ) peptide that is derived from amyloid-β precursor protein (APP). Current AD therapeutic strategies include improving cognitive processes and reducing brain Aβ levels. Cholinesterases inhibitors (ChE-Is) and memantine are the only FDA approved drugs for AD; they primarily provide symptomatic relief. A new series of AD drug candidates were designed to optimally match ChEI activity with APP/Aβ lowering action and generate agents that substantially lower brain amyloid and yet provide immediate symptomatic improvement: PosiphenTM and analogs. These agents lower APP and Aβ levels in culture, in animals and in humans, and possess slow release ChEI activities to allow administration of greater doses to thereby generate greater Aβ inhibition in the brain. Methods: Early AD patients are given Posiphen orally for 7 to 28 days and CSF and plasma samples are taken periodically. Measurements taken are: APP, Aβ42 and 40, tau and phospho tau, AChE, Posiphen and metabolites. Results: Posiphen has proven well tolerated in single and multiple-dose phase 1 clinical trials at high doses and achieves concentrations associated with substantial inhibition of Aβ in animal models. Ongoing studies are elucidating the mode of action of these compounds on the APP processing pathway compared to the AChEI activity in humans. Studies are also under way to better understand the AChEI activity of Posiphen and its demethylated metabolites. Conclusions: Preliminary results suggest that Posiphen and analogs are promising experimental drugs that combine a disease modifying component, inhibition of synthesis of APP mRNA resulting in lowered Aβ levels in the brain, with a symptomatic component and could have improved efficacy in humans.