It has long been widely acknowledged that microglial activation and other inflammatory mechanisms play a role in the pathogenesis of Alzheimer’s Disease. This, of course, was the rationale for the initiation of a nationwide study of the use of the Cox-2 inhibitor celecoxib(Celebrex®) for the treatment of AD, which study was prematurely stopped due to the realization that NSAIDs such as Vioxx® and Celebrex® had real potential toxicity. New evidence, however, continues to accumulate which suggests that the anti-inflammatory approach to AD may be viable, and may represent an alternative to the massive efforts, so far unsuccessful, to directly intervene in deposition, production, or removal of amyloid plaques from the human brain. Perhaps the most suitable question is the following: What if the anti-inflammatory approach was correct, but the wrong anti-inflammatory was studied?
Certainly, if we examine the rheumatoid arthritis model, no one is claiming that NSAIDS change the natural history of the disease. In contrast, the biologic anti-TNF anti-inflammatories (etanercept, infliximab, and adalimumab) have revolutionized the treatment of RA, and all have been shown to interrupt the joint destruction that occurs in this immune-based disorder, and favorably impact the natural history of the disease. Is it possible that the use of a similar novel and potent biologic anti-inflammatory could favorably impact the course of Alzheimer’s Disease?
Fascinating clues to the answer to this question are emerging. Just this past week a new paper from Virginia Lee, John Trojanowski, and Yasumasa Yoshiyama and their colleagues from the University of Pennsylvania reported dramatic success using the novel anti-inflammatory FK506 (tacrolimus) in a transgenic mouse model of AD[1]. These striking results join with the successful use of IVIG in the pilot study of Dodel[2] and our pilot results using etanercept[3] as three examples highlighting the promise of direct intervention in the inflammatory mechanisms of Alzheimer’s Disease through the use of a potent, new, biologic-based anti-inflammatory therapeutic.
The real question now is how long will it take for the Alzheimer research community to appreciate that this represents a promising alternative (or a complement) to the amyloid-based approaches which have for so long failed to come to fruition.
Perhaps we have now come full circle, and the time may soon come when the investigation of the use of novel, potent, biologic-based anti-inflammatories for the treatment of Alzheimer’s Disease has captured the attention and imagination of the Alzheimer community. Considering the magnitude of the unmet medical need, it may be hoped that the pride of those companies and researchers who have for so long toiled down the amyloid pathway without success can be put aside long enough for them to consider embracing an alternative approach.
1. Yoshiyama, Y., et al., Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model. Neuron, 2007. 53(3): p. 337-351.
2. Dodel, R.C., et al., Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry, 2004. 75(10): p. 1472-4.
3. Tobinick, E., et al., TNF-alpha Modulation for Treatment of Alzheimer's Disease: A 6-Month Pilot Study. MedGenMed, 2006. 8(2): p. 25.
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