Paradigm Shift: Excess TNF-Alpha Emerges as a Key Therapeutic Target in Alzheimer's Disease

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There is now substantial, and accumulating, basic science, genetic, and clinical evidence that excess tumor necrosis factor (TNF) is centrally involved in the pathogenesis of Alzheimer's disease.[1–26] New TNF data from the renowned Framingham Study is the most recent robust scientific evidence supporting a key role of excess TNF in Alzheimer's.[4] By negatively influencing synaptic regulation and amyloid, glutamate, NMDA, and inflammatory pathways, excess TNF, along with amyloid/tau, may constitute the “perfect storm” which attacks the brain and results in Alzheimer's progression.[1–26] The new recognition of the potential association of traumatic brain injury and Alzheimer's in professional football players, the increasing attention deservedly being given to the public health threat posed by Alzheimer's, and the increasing health burden posed by the growing ranks of our young veterans afflicted by traumatic brain injury underscores their unmet medical need. What is not yet widely recognized is that these disorders are united by the common involvement of excess TNF in their pathogenesis.[1–28]

What is most extraordinary is that there now exists a potent potential defense to this perfect storm: the biologic TNF inhibitor etanercept. Already the largest-selling biologic in the world, etanercept, when administered by a novel perispinal delivery method, has demonstrated unprecedentedly positive results in a pilot study, which has, until recently, remained largely unrecognized.[29,30] With publication of the new Framingham Study, increasing scientific validation, and recent acknowledgement of its promise by the prestigious Dana Alliance for Brain Initiatives, it is clear that perispinal etanercept for Alzheimer's disease merits careful, multicenter study.[1–26, 29–32] The contribution of excess TNF to Alzheimer's fits hand-in-glove with the amyloid hypothesis.[2–4, 9,13,14,16,18,21,23,25,30] TNF inhibition has potential beyond monotherapy for Alzheimer's; it may offer additive, or even synergistic, benefits in combination with anti-amyloid agents.[1–26, 30,32] The cascading evidence and unmet medical need together highlight the enormous promise which TNF inhibition for Alzheimer's represents.

That's my opinion, I'm Dr. Edward Tobinick, Assistant Clinical Professor of Medicine, UCLA.