AbstractBackgroundThe development and characterization of new mouse models late‐onset Alzheimer’s Disease (LOAD) are critical for understanding the progression of the pathology and as a platform for theevaluation of new drugs. The UCI MODEL‐AD project focuses on the development of LOAD mouse models based on human GWAS data.MethodWe evaluate each new modeldeveloped in our group by performing a comparative network analysis of hippocampal transcriptomes in order to relate changes in expression to other phenotypic changes. As part of our standard pipeline, we test each new GWAS variant model at the ages of 4 and 12 months crossed with 5XFAD mice to regular 5XFAD mice and GWAS variant‐only mice.ResultDifferential gene expression analysis allows us to quantify the impact of the ABI3, ABCA7, PICALM and TREM2 variants on the pathology. Each model that we have analyzed have both shared as well as unique gene modules. Several variants showed less transcriptional differences compared to wild type than 5xFAD at 4 months but increase inflammation at 12 months.ConclusionRNA transcriptome analysis combined with phenotypic characterization is essential to the characterization and identification of the most appropriate LOAD mouse model.