Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha (TNF-alpha) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers. The efficacy of etanercept, a biologic antagonist of TNF-alpha, delivered by perispinal administration, for treatment of Alzheimer's disease over a period of six months has been previously reported in a pilot study. This report details rapid cognitive improvement, beginning within minutes, using this same anti-TNF treatment modality, in a patient with late-onset Alzheimer's disease. Rapid cognitive improvement following perispinal etanercept may be related to amelioration of the effects of excess TNF-alpha on synaptic mechanisms in Alzheimer's disease and provides a promising area for additional investigation and therapeutic intervention.