PROJECT SUMMARY DISEASE MODELING PROJECT (DMP) The overall goal of the Indiana University/The Jackson Laboratory Alzheimer's Disease Precision Models Center (IU/JAX ADPMC) is to develop, characterize and distribute more precise preclinical models for Alzheimer's disease (AD). The IU/JAX ADPMC Disease Modeling Development and Phenotyping Project will use CRISPR genome editing to generate mouse models that carry different combinations of human risk alleles for late-onset AD (LOAD). In addition, some of the most widely used existing models for AD will be fully characterized to develop more clinically relevant phenotyping platforms. We have assembled a team of experts in human and mouse genetics, mouse models of AD, genome editing, genomic approaches to understand complex diseases (including sequencing and computational modeling) and various biological processes implicated in AD (including APP processing, cholesterol trafficking, neuroinflammation and vascular biology). We have three specific aims. Aim 1 is to fully characterize APP/PS1, 5xFAD and hTau, three of the most widely used mouse models of AD. APP/PS1 and 5xFAD carry a combination of mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) that cause early-onset AD (EOAD) in humans. APP/PS1 and 5xFAD have been widely used to study amyloidosis and neuroinflammation. hTau carries human wild type microtubule associated protein Tau (MAPT) in the absence of mouse Mapt and develops age-related MAPT hyperphosphorylation, aggregation, and some neurodegeneration. We will also extensively characterize a new model of LOAD that we have created that carries the two greatest genetic risk factors for LOAD, APOE?4 and TREM2R47H. We will prioritize clinically relevant endpoints including in vivo imaging, blood and tissue biomarkers and genomics, and compare these to more traditionally used endpoints such as behavioral assays that have not proven reliable when translated to the clinic. In Aim 2, we will generate mice carrying 40 new allelic variants identified through the Bioinformatics and Data Management Core and use an efficient in vivo screening strategy to determine the promising models to pass through to deep phenotyping. In the early years of the center we will prioritize understanding GWAS variants (ABCA7, BIN1 and CR1) as well as variations in two genes identified by us from analyses of the AD Sequencing Project (NANOS1) and AD Neuroimaging Initiative (IL1RAP). All models created will be made available at the earliest opportunity through the JAX AD Mouse Mutant Resource (ADMMR). In Aim 3, we will fully characterize models that show important AD- relevant phenotypes including amyloid deposition, tau pathology and neurodegeneration using the deep phenotyping strategy described in Aim 1. All new findings will be validated in human tissues. Throughout this funding period, we anticipate 40 new models will be generated and distributed, and up to 8 new and 4 existing models will be extensively characterized. Our strategy closely integrates human and mouse data, so these new AD models will show a high degree of clinical translatability for preclinical testing of new therapeutic targets.