Mega-Analysis of Gene Expression in Mouse Models of Alzheimer's Disease

While multiple studies have been conducted of gene expression in mouse models of Alzheimer's disease (AD), their findings have not reached a clear consensus and have not accounted for the potentially confounding effects of changes in cellular composition. To help address this gap, we conducted a re-analysis based meta-analysis (mega-analysis) of ten independent studies of hippocampal gene expression in mouse models of AD. We used estimates of cellular composition as covariates in statistical models aimed to identify genes differentially expressed (DE) at either early or late stages of progression. Our analysis revealed changes in gene expression at early phases shared across studies, including dysregulation of genes involved in cholesterol biosynthesis and the complement system. Expression changes at later stages were dominated by cellular compositional effects. Thus, despite the considerable heterogeneity of the mouse models, we identified common patterns that may contribute to our understanding of AD etiology. Our work also highlights the importance of controlling for cellular composition effects in genomics studies of neurodegeneration.