In the present study, we not only characterized a novel circRNA circAPP, that is upregulated in Aβ-treated microglia and the hippocampus of APP/PS1 mice but also investigated the regulatory roles of circAPP and its downstream mediators miR-1906 and CLIC1 in microglial polarization in vitro and in vivo, and AD pathology and cognitive function in vivo. The gene discussed is CLIC1; the disease is Alzheimer disease.