Alzheimer's disease is characterized by neurofibrillary tangles composed of aggregates of truncated and hyperphosphorylated tau protein, but the mechanisms of their formation are understood poorly. The authors showed that in a mouse model of Alzheimer's disease, deletion of asparagine endopeptidase (AEP; a lysosomal cysteine proteinase) reduced tau hyperphosphorylation and cognitive deficits associated with Alzheimer's disease. Adeno-associated viral delivery of degradation-resistant tau had a similar effect, and suggests a role for AEP in tau-associated neurodegeneration.