Andrographolide (AP), a diterpenoid compound extracted from Andrographis paniculata, has been shown to be a promising therapy for Alzheimer's disease (AD) in preclinical studies, but the involved mechanisms still need to be clarified. Here we showed that AP improved cognition function and reduced amyloid-β (Aβ) plaque accumulation of 5×FAD transgenic mice by mitigating microglial senescence.