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

Edward Tobinick, MD  
Medscape General Medicine.  2007;9(3):17.  ©2007 Medscape
Posted 07/20/2007 
 

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. 
 
____________________________________
Readers are encouraged to respond to the author at layon@ufl.edu or to  Paul 
Blumenthal, MD, Deputy Editor of MedGenMed, for the editor's  eyes only or for 
possible publication via email:  pblumen@stanford.edu
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Edward Tobinick, MD, Assistant Clinical Professor  of Medicine, UCLA, Los 
Angeles, California; Medical Director, Institute  for Neurological Research (a 
private medical group, inc.), Los Angeles,  California

Author's email: _etmd@ucla.edu_ (mailto:etmd@ucla.edu) 

Disclosure: Edward Tobinick, MD, had disclosed that he  has multiple issued 
and pending U.S. and foreign patents which describe  the use of etanercept and 
other anti-TNF biologics for the treatment of  neurological disorders, 
including, but not limited to, Alzheimer's Disease  and traumatic brain injury. The 
issued patents include, but are not  limited to, U.S. patents 6015557, 6177077, 
6419934, 6419944, 6537549,  6982089, and 7214658. In addition the author owns 
stock in Amgen, the  manufacturer of etanercept.