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Tumour Necrosis Factor Modulation for Treatment of Alzheimer’s Disease

Rationale and Current Evidence

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Abstract

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.

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Notes

  1. TNF as used herein is synonymous with TNFa. The nomenclature for TNF has changed over time. Upon recommendation of the 7th International TNF Congress (17–21 May 1998; Hyannis, MA, USA),[3] the names for TNFα and TNFβ were changed to TNF and lymphotoxin-a (LTα), respectively.

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Acknowledgements

No outside funds were received in connection with the preparation of this manuscript. The author, Edward Tobinick MD, owns stock in Amgen, the manufacturer of etanercept, and has multiple issued and pending US and international patent applications describing the use of perispinal etanercept for neurological disorders, including but not limited to Alzheimer’s disease and other forms of dementia. The issued patents include, but are not limited to, US patents 6,982,089; 7,214,658; and Australian patent 758,523. The author appreciates the contributions of Hyman Gross, MD and Alan Weinberger, MD, both of whom were co-authors of the pilot study that investigated the clinical effects of perispinal etanercept for Alzheimer’s disease; and the contribution of Arthur Tobinick, who performed the videography that was included as part of several of the articles that have been published on perispinal etanercept for Alzheimer’s disease and related forms of dementia.

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    Edward Tobinick (MD)

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Tobinick, E. Tumour Necrosis Factor Modulation for Treatment of Alzheimer’s Disease. CNS Drugs 23, 713–725 (2009). https://doi.org/10.2165/11310810-000000000-00000

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