Donepezil inhibited the phosphorylation of the AKT/MAPK signaling pathway, NLRP3 inflammasome, and transcription factors NF-kB/STAT3 induced by LPS, thereby reducing neuroinflammatory responses. Donepezil significantly alleviated LPS-induced microglial activation, microglial density/morphology, and levels of pro-inflammatory cytokines COX-2 and IL-6. In the Alzheimer's disease mouse model (5xFAD mice), Donepezil markedly decreased the activation, density, and morphology of Aβ-induced microglia and astrocytes. This evidence concerns the gene NFKB1 and early-onset autosomal dominant Alzheimer disease.