Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis. Previous studies comparing AD versus control using bulk brain tissue samples have not considered cell composition changes in AD brains that can cause transcriptional changes not due to transcriptional regulation.
Using five large transcriptomic datasets, we mined conserved gene co-expression network modules, and applied differential expression and differential co-expression analysis on the modules in AD versus control brains. Combined with cell type deconvolution analysis, we addressed the question of whether the module expression changes are due to altered cellular composition or transcriptional regulation. Our findings were validated using four additional datasets.
We discovered that the increased expression of microglia modules can be explained by increased microglia population in AD brains rather than gene upregulation. In contrast, the decreased expression and perturbed co-expression in AD neuron modules are due to both neuron loss and regulation of neuronal pathways and several transcriptional factors are identified for such regulation. Similarly, the strong changes in expression and co-expression in astrocyte modules can also be attributed to a combinatory effect from astrogliosis and astrocyte gene activation in AD brains. The astrocyte modules expressions also strongly correlated with the clinicopathological biomarkers.
In summary, we demonstrated that combinatorial analysis is a powerful approach to delineate the origin of transcriptomic changes in bulk tissue data, which leads to a deeper understanding of key genes/pathways in AD.