Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagysubstrate and which is causatively linked to AD, both in vitro and invivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models.CALM influences autophagy byregulating the endocytosis of SNAREs, such as VAMP2, VAMP3and VAMP8, which have diverseeffects on different stages of the autophagy pathway, from autophagosome formationto autophagosome degradation. The gene discussed is PICALM; the disease is Alzheimer disease.