AD is a progressive neurodegenerative disorder with symptoms usually manifesting later in life in patients over 65 years of age, so called late-onset or sporadic AD. The World Alzheimer’s Report projects that AD related dementia will rise to 76 million cases by 2030 and 132 million cases by 2050. In the US alone it is estimated that in 2018, Alzheimer’s and other dementias cost the nation $277 billion. By 2050, costs could rise as high as $1.1 trillion. Existing treatments do not prevent or even slow AD progression and they do not target the under lying pathology of AD. Novel therapeutics that prevented or even slowed AD progression would be of immense economic importance and benefit a huge, and growing, number of patients and their families. Atux Iskay LLC proposes to develop a novel class of compounds as AD therapeutics that act by increasing and normalizing abnormally suppressed protein phosphatase 2A (PP2A) activity in AD, and thereby directly target the underlying pathology of the disease. There is a large body of evidence that PP2A activity is suppressed in AD and this underlies tau-hyperphosphorylation and promotes amiloidogenic APP processing that characterizes the central, linked, disease processes in AD. Atux Iskay LLC proposes to develop lead compounds that bind and allosterically activate PP2A, thereby suppressing tau phosphorylation and Ab secretion. The compounds are novel, medicinally tractable, drug-like structures, which are orally bioavailable and partition into the CNS after oral dose. Prototype compounds are active in cellular models of tau- phosphorylation and Ab secretion, show neuroprotective effects in ex vivo electrophysiology models of synaptic plasticity and are active in an in vivo rat model of AD where they ameliorate tau and Ab pathologies and rescue behavioral and cognitive deficits induced in the disease model. The objectives of the project are Aim #1. Compounds in published studies are constrained tricyclic sulfonamides: a compound in this series will be selected as development candidate with improved metabolic stability and bioavailability. Aim #2. Identification of alternate scaffolds and chemotypes, as back-up compounds series proprietary to Atux Iskay LLC. File provisional patent(s) on new compound series. Aim #3. Evaluation in vitro and in ex-vivo electrophysiology experiments to examine protective effects of new PP2A activators versus Ab and phospho- tau mediated neurotoxicity. Lead compound(s) will be equipotent with prototypes in vitro and be suitable for once daily dosing in animal models. Successful implementation will provide Atux Iskay LLC with a lead compound and back-ups for further pre-clinical in the context of a Phase 2 SBIR project. The overall objective are new, first in class, disease modifying AD therapeutics that will benefit AD patients and reduce the enormous and growing burden of Alzheimer’s Disease Related Dementia.