VALIDATION OF A SIMPLE SEVERITY SCALE FOR ASSESSING ARIA-E

Background:Many amyloid-modulating clinical trials have failed and it is important to identify key problems in order to avoid making the same mistakes. In addition to disease state or insufficient target engagement, imbalances in comedications or genotypes in different treatment arms can be another confounding factor. In the absence of actual clinical data, we used a Quantitative Systems Pharmacology (QSP) platform to simulate the pharmacodynamic interaction of AChE-I, memantine and the APOE, COMTVal158Met and SCL6A4 5-HTT LPR genotype with Ab-modulating therapeutic interventions on cognitive effects. Methods: QSP is a mechanism-based and humanized computer simulation of Ab aggregation and the interaction of Ab40 and Ab42 oligomers on glutamate and a7 nAChR neurotransmission in an ADAS-Cog calibrated cortical neuronal network over 78 weeks. The platform recapitulates the unexpected reported negative pharmacodynamic interaction between Ab load and scopolamine on cognition in MCI subjects. Human imaging studies are used to implement APOE and SCL6A4 genotypes and the dose-response of AChE-I and memantine. Results: The model captures the anticipated lack of