ABSTRACT The goal of the Disease Model Development and Phenotyping Project (DMP) is to develop novel mouse models of late-onset Alzheimer’s disease (LOAD), to deeply phenotype these models, and to make all data and mouse strains available to enable researchers to select the optimal mouse model and timepoints for therapeutic and intervention testing, as well as for the testing of hypotheses concerning mechanisms of LOAD. During the past five years, we have generated and deeply phenotyped mice with one component of our base genetic platform in which the Aß region of the App gene was humanized, and we have recently introduced the second component, a humanized MAPT (TAU) locus produced via gene-replacement. We have also used CRISPR and genome replacement to model and validate nine GWAS identified LOAD risk-variants and have analyzed mice with each variant both on a wild-type and 5xFAD background to determine their effects on plaque generation and damage exerted on the brain in response to pathology. In this continuation, we will use the results of these analyses, plus input from the FGBDMC and the literature, to identify combinations of LOAD risk variants most likely to phenocopy LOAD and introduce them on two complementary hAb-KI, hTAU, hAPOE4 platform lines, designed to mimic sub-types of AD that have been recently defined. These models will be characterized across their lifespans to evaluate the effects of variants on the development of pathologies and subsequent tissue damage in combination with aging. The UCI MODEL-AD group utilizes a comprehensive approach to evaluate these LOAD mouse models, which includes behavioral/cognitive assessment, electrophysiological analysis, super- resolution synaptic imaging, neuroimaging, bulk and single-cell RNA-seq, single cell level spatial transcriptomic analysis, proteomics, and microbiome and metabolome investigations including screening for novel biofluid markers associated with progression to LOAD. UCI MODEL-AD will leverage the resources of our NIA-funded Alzheimer’s Disease Research Center combined with the Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP-AD) and other human AD datasets to facilitate alignment of data obtained from these mouse models to the human condition to identify the best mouse models for use by the international AD research community. All data and models will be made available without restrictions, via The Jackson Labs (JAX), and data will be explorable via the modeladexplorer.org website, and raw data freely available for download via the AD Knowledge Portal.