Taken together our findings show that R47H variant microglia express a deficit in upstream and down-stream signalling responses, culminating in their inability to activate the NLRP3 inflammasome in response to a TREM2 ligand, PS, and a reduced ability to activate the inflammasome in response to a classic inflammatory/priming signal, both of which have ramifications for microglial responses in AD. Here, NLRP3 is linked to Alzheimer disease.