Subtle changes in brain expression modules in Alzheimer’s disease TREM2 carriers compared to non-carriers

Background: Rare heterozygous coding variants with a large effect on the risk of developing late-onset Alzheimer's disease (similar to ApoE4, OR 2.90-5.05) have been identified in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene. However, little is known about the mechanisms through which Trem2 maladjustment may lead to AD Methods: We performed differential expression and co-expression network analysis on samples obtained from 5 (mainly 2) brain areas from individuals carrying the TREM2 variant known to increase the risk of Alzheimer’s and others using RNA-Seq to obtain a systems level view of the effects of the TREM2 mutation Results: The absence of Trem2 has a stronger effect at an earlier age with the number of differential expressed (DE) genes being 17-fold greater at 4 months than at 8 months in cortex. By integrating DE genes and network analysis we discovered gene clusters associated with the disruption of blood vessel formation at 4 months of age and protein targeting primarily affecting the hippocampus at 8 months. Further integration of cell type and ontology information revealed a large disruption of a gene module enriched for endothelial cell markers coinciding with the module enriched for neuron cell markers having weaker connections to modules with oligodendrocyte and astrocyte identities. The module with neuronal identity has decreased expression only in the KO where it has closer association with a new module enriched for phagocytic functions Conclusions: Combining gene co-expression and differential expression analysis on brains of carriers of TREM2 mutations we demonstrate that the presence of damaging TREM2 mutation produce subtle disruptions.