The accumulation of amyloid-β protein into plaques is a characteristic feature of Alzheimer's disease. However, the contribution of amyloid-β plaques to neuronal dysfunction is unknown. We compared intracellular recordings from neocortical pyramidal neurons in vivo in APP-Sw (Tg2576 transgenic mice overexpressing amyloid precursor protein with the Swedish mutation) transgenic mice to age-matched nontransgenic cohorts at ages either before or after deposition of cortical plaques. We show that the evoked synaptic response of neurons to transcallosal stimuli is severely impaired in cortex containing substantial plaque accumulation, with an average 2.5-fold greater rate of response failure and twofold reduction in response precision compared with age-matched nontransgenic controls. This effect correlated with the presence of amyloid-β plaques and alterations in neuronal process geometry. Responses of neurons in younger APP-Sw animals, before plaque accumulation, were similar to those in nontransgenic controls. In all cases, spontaneous membrane potential dynamics were similar, suggesting that overall levels of synaptic innervation were not affected by plaques. Our results show that plaques disrupt the synchrony of convergent inputs, reducing the ability of neurons to successfully integrate and propagate information.