Predicting Relevant Microglia‐Associated Cell–Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1

ABSTRACT Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell–cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1 , and while this pathway was also present in control samples, microglia–microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia–microglia signaling predict AD‐specific induction of GAS6‐AXL signaling (from inflammatory and ribosomal microglia), and SPP1‐ITGAV/ITGB5 signaling (from disease‐associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.