Alzheimer’s disease and more than 20 other dementias and movement disorders collectively known as tauopathies are defined by intracellular filamentous inclusions containing the microtubule-associated protein tau. However, how tau is converted from soluble monomers to insoluble aggregates in these diseases remains unknown. Zhang et al. analyzed more than 70 human tripartite motif (TRIM) proteins and identified several that could reduce tau aggregates (see the Perspective by Noble and Hanger). Among these, TRIM11 was able to maintain tau in its functional soluble form in a manner mechanistically distinct from canonical protein quality control factors. TRIM11 was found to be markedly down-regulated in sporadic Alzheimer’s disease brains, potentially contributing to pathogenesis. Indeed, intracranial adeno-associated viral delivery of TRIM11 provided strong protection against tau pathology, cognitive decline, and motor defects in multiple mouse models of tauopathies.