Project Summary/Abstract The goal of MODEL-AD is to generate improved mouse models of sporadic, late-onset Alzheimer's disease (AD). Ideally, such mice will develop facets of human AD pathology including neuritic plaques, neurofibrillary tangles, and widespread cortical and hippocampal neurodegeneration in advanced age. The C57BL/6J (B6J) mouse strain background has been selected as a uniform inbred strain to use for the production of mouse models by MODEL-AD. However, there is concern regarding the validity of using a single genetic background of mice to model a complex and polygenic human disease such as AD. Indeed, recent data from the UCI MODEL-AD DMP and that of our IU/JAX collaborators provide independent support which strongly suggests that the standard B6J mouse genetic background is not optimal for the formation of plaques or for neurodegeneration. We propose to test the hypothesis that genetic diversity affects pathology in mouse models of late-onset AD by using a unique genetic resource ? the Collaborative Cross (CC) strains. CC reference strains represent a multi-parental recombinant inbred panel derived from eight laboratory mouse inbred strains, which allow standardization of studies to investigate how genetic diversity impacts pathology. Importantly, the genetic diversity within CC lines is similar to that found in human populations. To address the concern of limiting MODEL-AD models to a single genetic background, we request a supplement to investigate the effect of introducing genetic diversity into the hAb-KI/Trem2<R47H>/ApoE4 mouse on development of AD phenotypes. We anticipate that this study will identify genetic backgrounds with increased diversity that are more conducive to plaque formation and neurodegeneration compared to B6J and hence provide mice that more accurately develop AD pathology as they age. Mouse lines with optimum AD pathology will be sent to JAX for distribution to the international community.