PROJECT SUMMARY/ABSTRACT OVERALL COMPONENT Alzheimer’s disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of basic biological mechanisms underlying AD, we do not yet know how to prevent AD or have an approved disease modifying intervention. Animal models of Alzheimer’s disease (AD) have provided important insights into the pathophysiology of disease and suggested potential avenues for therapies; however, translation of these findings to the clinic has been largely unsuccessful. The MODEL-AD Consortium was initiated to generate and validate the next generation of mouse models of late-onset Alzheimer’s disease (LOAD) as well as to perform rigorous preclinical testing of the most promising therapeutics in these models. Based on advances in human disease characterization driven by genetic, molecular, and imaging studies, we have created more than 40 LOAD mouse models carrying genetic risk variants. These models have been characterized using the same molecular and imaging modalities used in the clinic, revealing LOAD-relevant phenotypes not observed in prior mouse models. The IU/JAX/PITT MODEL-AD Center is now poised to leverage these existing models, protocols, and data to further our mission of creating translatable preclinical tools. The Indiana University (IU)/Jackson Laboratory (JAX)/University of Pittsburgh (IU/JAX/PITT) will leverage IU’s and PITT’s strengths in neurodegenerative research including 30+ years as an NIA-supported Alzheimer’s Disease Center (ADRC) and considerable expertise in preclinical drug testing with JAX’s eight decades of expertise in mammalian genetics and disease modeling to develop, validate and disseminate new, precise animal models of AD. In addition, the IU/JAX/PITT MODEL-AD Center contains Sage Bionetworks to provide expertise in data organization and dissemination. The IU/JAX ADPMC brings together an international, multi-disciplinary team— including geneticists and genetics technology experts, quantitative and computational biologists, clinical experts in AD and neuroimaging, pharmacologists and world leaders in the development of precision animal models of disease—that possesses the collective ability to foresee disease modeling needs as they emerge on the international stage. This will allow the IU/JAX ADPMC to serve the AD scientific community effectively and efficiently. Ultimately, this will accelerate the application of advances in animal models for the greatest possible medical benefit. The Specific Aims of the IU/JAX/PITT MODEL-AD Center are: Aim 1: Prioritize genetic variants, analyze model data, and broadly disseminate results through data sharing and online analytics. Aim 2: Creating and characterizing novel LOAD models Aim 3: Screening of novel compounds through the PTC pipeline. Aim 4: Coordinate activities within the center, the MODEL-AD consortium, and across the broader community of AD/ADRD researchers.

PROJECT NARRATIVE OVERALL COMPONENT Alzheimer’s disease is a major cause of death and disability in the United States and the National Alzheimer’s Project Act seeks to identify a treatment or prevention for Alzheimer’s disease (AD). In order to meet this ambitious goal, the interdisciplinary Indiana University/Jackson Laboratory/University of Pittsburgh (IU/JAX/PITT) MODEL-AD Center seeks to continue generating and characterizing novel animal models of AD, assessing the relevance of these to model to human disease, and developing a precision preclinical testing pipeline through which novel therapies can be tested to greatly accelerate the process by which therapies are successfully moved forward to human AD clinical trials. Importantly, the IU/JAX/PITT Center will generate new AD modeling processes and pipelines, data resources, research results and models that will be swiftly shared via existing infrastructure at the participating institutions and through the AD Knowledge Portal, academic medical centers, research institutions and the pharmaceutical industry worldwide.