Alzheimer disease is associated with progressive neurodegeneration and cognitive impairment — notably, hippocampus-related memory deficits — and the formation of hallmark molecular pathologies — including amyloid-β plaques — in the brain. It is currently unclear whether spreading molecular pathology or network dysfunction caused by localized pathology is sufficient to cause progressive cognitive deficits in this disease. To examine the latter possibility, Viana da Silva et al. created mice that expressed a mutant form of human amyloid precursor protein (APP), from which amyloid-β is derived, only in the principal cells of the CA3 hippocampal region (CA3-APP mice).