Transcriptomic profiling of APOE4/Trem2*R47H mouse models for late‐onset Alzheimer’s disease

Abstract Background Late‐onset Alzheimer’s disease (LOAD) is the leading cause of dementia in the elderly. However, most transgenic animal models are based on rare, early‐onset AD genes which have not been great preclinical models as they may not sufficiently capture the full transcriptomic signatures and complete neuropathology of disease. Animal models based on LOAD‐associated genes are necessary to connect common genetic variation with LOAD transcriptomes. Method We performed transcriptomic analysis at 4, 8, 12 and 24 months of age on whole brain samples from APOE4 KI mouse, carrying a humanized version of the prominent APOE4 genetic risk factor for LOAD, and the Trem2*R47H mouse, carrying a rare deleterious variant R47H allele of Trem2 . In addition, a mouse model expressing both human APOE4 and the Trem2*R47H mutation was used to compare the transcriptional effects in mice carrying both variants to mice carrying only a single risk allele and B6 controls.We compared mouse modules with human postmortem brain modules from the Accelerating Medicine’s Partnership for AD (AMP‐AD) to determine the AD relevance of risk genes Result Differentially expressed genes in these mice were significantly enriched in multiple AD‐related pathways, including immune response, osteoclast differentiation, metabolism, and mRNA/protein processing. We also observed age related changes, specifically in Trem2*R47H mice, such as more differentially expressed genes and significant differential splicing events compare to the APOE4 mouse models.Further, these mouse models overlapped with immune, myelination, neuronal, and DNA repair related AMP‐AD modules. Conclusion We have characterized three novel mouse models of LOAD at young and advanced ages and observed sex as well as age‐specific transcriptional changes. These mouse models exhibited similar transcriptional changes as seen in clinical samples. Hence, this double mutant mouse model will be used as a sensitized genetic background for further addition of human AD risk variants to model late‐onset Alzheimer’s disease in mice.