It is currently unclear which forms of the protein tau contribute to Alzheimer disease (AD) pathology, but Δtau314, which is produced following caspase 2-mediated tau cleavage, is elevated in the brains of cognitively impaired mice and humans with AD. Here, in vitro expression of a mutant form of tau that was resistant to caspase 2 cleavage reduced tau accumulation in dendritic spines and tau-induced synaptic dysfunction. Moreover, knockdown of caspase 2 expression in the rTg4510 mouse tauopathy model improved long-term memory in mice with existing deficits; thus, caspase 2 inhibition might have therapeutic potential in human tauopathies.