Among the susceptibility loci for Alzheimer disease that have been identified in genome-wide association studies, PICALM is one of the most significant, and a new study has demonstrated that reduction in its expression increases tau pathology. PICALM encodes phosphatidylinositol binding clathrin assembly protein (PICALM), which is involved in endocytosis and autophagy. In their study, Ando et al. showed that levels of soluble PICALM were reduced and autophagy was impaired in post-mortem brains from humans with tau-associated frontotemporal dementia. Furthermore, in a mouse model that expresses mutant human tau, haploinsufficiency of Picalm led to higher levels of pathological tau, more severe motor deficits and abnormal autophagy. The evidence demonstrates the link between PICALM expression and tau pathology and indicates a mechanism for the link between PICALM and Alzheimer disease.