Project Summary/Abstract A key goal of the UCI MODEl-AD Disease Model Development and Phenotyping Project (DMDPP) is to generate and phenotype new models of Alzheimer's disease (AD) that better recapitulate late onset AD (LOAD). The LOAD models will be generated on a platform of humanized Ab and tau, two hallmark pathological proteins found in AD. Once humanized, we will then introduce AD-risk associated polymorphisms in genes to test their ability to drive characteristics of LOAD. The ultimate goal is the production and characterization of a mouse that can be used to explore the key drivers of AD pathology in the aging process, both genetic and environmental. Standard measures of Aβ40 and Aβ42 and total and phospho-tau levels, inflammatory markers will be performed for each genotype and age. In addition, neurofilament light, a newly investigated translatable biomarker, can be quantified in these animals. This involves, at a minimum, analysis of 1000 samples of plasma, hippocampus and cortex for every mouse model in the next 3 years. The Meso Quickplex SQ120 instrument provides several advances compared to pre-existing enzyme-linked immunosorbent assay (ELISA) system, as it enables simultaneous tests on a single sample and it is a high-performance electrochemilunescence immunoassay. Furthermore, the same system is being used in the other MODEL-AD centers to obtain these endpoints in their phenotyping protocols, and thus it is important for UCI to harmonize with the other consortium members.