PROJECT SUMMARY PRECLINICAL TESTING CORE (PTC) The Preclinical Testing Core (PTC) of the IU/JAX Alzheimer’s Disease Precision Models Center will establish and validate a preclinical testing screening strategy pipeline with predetermined go/no-go decision points using pharmacokinetics, pharmacodynamic biomarkers and functional assessments in biologically and pathologically relevant AD mouse models that allow standardized and unbiased assessments of potential therapeutic agents. The Core is led by experts in preclinical imaging, neuropharmacology, and animal model characterization at IU’s Center for Neuroimaging and JAX’s Mouse Neurobehavioral Phenotyping, In Vivo Imaging, and Physiology Core facilities, and supported by IU’s Clinical Pharmacology Analytical Core. The pipeline’s primary and secondary screens focus on generating pharmacokinetic (PK) and pharmacodynamic (PD) biomarker assessments in two new generation AD mouse models with construct validity. Only test compounds that demonstrate target engagement in the biomarker screens will move to tertiary screening for in vivo symptom modifying effects and determination of the novel compound’s therapeutic window. The specific aims of the PTC are (1) the establishment of a standardized testing pipeline, the development of the assay protocols and methods, the creation of the data repository and back-translating clinical compound failures; (2) validating the pipeline with two compounds currently in clinical trials in two biologically and pathologically relevant animal models; (3) the evaluation of novel test compounds through the pipeline which allows investigators in the greater AD research community with unprecedented access to a validated pipeline, standardized testing protocols, and resources to screen compounds of interest.