This study for the first time revealed the association between circRNA and microglia-driven AD pathogenesis, uncovered the essential role of circDlg1/PDE4B axis in microglia, and indicated the scaffold role of circDlg1 in Smurf2-mediated ubiquitination of PDE4B by interacting with the unique N-terminal TD of PDE4B, thus providing new insight into the development of innovative therapeutic strategies tailored to circDlg1-involved degradation of PDE4B for ameliorating microglial response to Aβ and neuroinflammation in AD. This evidence concerns the gene PDE4B and Alzheimer disease.