Tumour necrosis factor (TNF), a key regulator of varied physiological mechanisms in multiple organ systems, is an immune signalling molecule produced by glia, neurons, macrophages and other immune cells. In the brain, among other functions, TNF serves as a gliotransmitter, secreted by glial cells that envelope and surround synapses, which regulates synaptic communication between neurons. The role of TNF as a gliotransmitter may help explain the profound synaptic effects of TNF that have been demonstrated in the hippocampus, in the spinal cord and in a variety of experimental models. Excess TNF is present in the CSF of individuals with Alzheimer's disease (AD), and has been implicated as a mediator of the synaptic dysfunction that is hypothesized to play a central role in the pathogenesis of AD. TNF may also play a role in endothelial and microvascular dysfunction in AD, and in amyloidogenesis and amyloid-induced memory dysfunction in AD. Genetic and epidemiological evidence has implicated increased TNF production as a risk factor for AD. Perispinal administration of etanercept, a potent anti-TNF fusion protein, produced sustained clinical improvement in a 6-month, open-label pilot study in patients with AD ranging from mild to severe. Subsequent case studies have documented rapid clinical improvement following perispinal etanercept in both AD and primary progressive aphasia, providing evidence of rapidly reversible, TNF-dependent, pathophysiological mechanisms in AD and related disorders. Perispinal etanercept for AD merits further study in randomized clinical trials.