on the study by
Richard Chou et al. CNS Drugs, 2016 Jul 28. [Epub ahead of print]
Treatment for Rheumatoid Arthritis and Risk of Alzheimer’sDisease: A Nested Case-Control Analysis
Compelling new data published online in the journal CNS Drugs documents a substantial and significant decreased risk of developing Alzheimer’s disease (AD) in individuals with rheumatoid arthritis (RA) treated with the drug etanercept (1).
Etanercept, approved for treating several immune-mediated disorders, including rheumatoid arthritis, selectively binds to and neutralizes tumor necrosis factor (TNF). TNF is a cytokine that not only upregulates the inflammatory response, but also regulates key brain functions by modulating communication between neurons (synaptic transmission) (2-4) (Cover Image/Figure).
Dartmouth Assistant Professor Richard Chou and colleagues studied a database of records of 8.5 million commercially insured adults in the U.S., matching subjects with RA (controls) with those with RA and AD (cases) (1). They assessed the relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab.
They found that only treatment with etanercept was associated with a significantly decreased risk of AD in RA patients. They concluded that there was an increased risk of AD in the studied RA population; that the relative risk of AD among RA subjects was lowered in those exposed to etanercept; and that etanercept shows promise as a potential treatment for AD (1).
This new epidemiologic data is consistent with more than two decades of evidence suggesting a key role of neuroinflammation in the pathogenesis of Alzheimer’s. In 1996 Chou, working under the mentorship of Robert Spengler PhD, along with Tracey Ignatowski, at SUNY Buffalo, published research illuminating brain effects of TNF (5).
In 2003 Kaj Blennow MD and colleagues in Sweden reported an association between elevated levels of TNF in the cerebrospinal fluid and progression of mild cognitive impairment to AD (6). In 2006 Edward Tobinick MD and colleagues in the U.S. were the first to publish clinical trial data providing evidence of the therapeutic activity of etanercept against Alzheimer’s disease, using a novel method of etanercept administration, perispinal delivery (2, 7, 8).
Other neuroscientists, including Sue Griffin PhD at the University of Arkansas, Nigel Grieg PhD and colleagues at the NIH, Ian Clark PhD at the Australian National University and Yong Shen at the Roskamp Institute in Florida, have provided additional scientific rationale for targeting excess TNF and neuroinflammation in AD (9-17). In 2012 and 2014, international groups of neuroscientists reviewed the scientific evidence supporting excess TNF as a therapeutic target in individuals with AD and after stroke, respectively (18, 19).
Conclusion: In a field that is accustomed to continuing disappointment (20), the new study by Chou and colleagues provides important new data that supplements the accumulating evidence pointing to targeting neuroinflammation, specifically excess TNF, as a promising new direction for AD research.
Acknowledgment: No funding was received in connection with this manuscript.
Conflict of Interest Statement: The author has multiple patents, assigned to TACT IP LLC, describing methods of perispinal delivery of etanercept and other drugs for treatment of neurological, spinal, opthalmic, oncologic, and otolaryngologic indications, including Alzheimer’s disease, including but not limited to U.S. patents 6419944, 6537549, 6982089, and 8900583. Dr. Tobinick is the CEO of TACT IP, LLC and founder of the Institute of Neurological Recovery®, a medical practice that utilizes perispinal etanercept as a therapeutic modality and also train physicians.
- Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for Rheumatoid Arthritis and Risk of Alzheimer’s Disease: A Nested Case-Control Analysis. CNS Drugs. 2016.
- Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res. 2007;4(5):550-2.
- Cavanagh C, Colby-Milley J, Farso M, Krantic S, Quirion R. Early molecular and synaptic dysfunctions in the prodromal stages of Alzheimer’s disease: focus on TNF-alpha and IL-1Beta. Future Neurology. 2011;6(6):757-69.
- Santello M, Volterra A. TNFalpha in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638-47.
- Ignatowski TA, Chou RC, Spengler RN. Changes in noradrenergic sensitivity to tumor necrosis factor-alpha in brains of rats administered clonidine. J Neuroimmunol. 1996;70(1):55-63.
- Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74(9):1200-5.
- Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed. 2006;8(2):25.
- Tobinick EL. Perispinal Delivery of CNS Drugs. CNS Drugs. 2016;30(6):469-80.
- Griffin WS. Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation. 2008;5:3.
- Di Bona D, Candore G, Franceschi C, Licastro F, Colonna-Romano G, Camma C, et al. Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer’s disease. Brain Res Rev. 2009;61(2):60-8.
- Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease. Pharmacol Ther. 2010;128(3):519-48.
- McNaull BB, Todd S, McGuinness B, Passmore AP. Inflammation and anti-inflammatory strategies for Alzheimer’s disease–a mini-review. Gerontology. 2010;56(1):3-14.
- Frankola KA, Greig NH, Luo W, Tweedie D. Targeting TNF-alpha to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases. CNS Neurol Disord Drug Targets. 2011;10(3):391-403.
- Cheng X, Shen Y, Li R. Targeting TNF: a therapeutic strategy for Alzheimer’s disease. Drug Discov Today. 2014;19(11):1822-7.
- Butchart J, Brook L, Hopkins V, Teeling J, Puntener U, Culliford D, et al. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology. 2015;84(21):2161-8.
- Clark IA, Vissel B. A Neurologist’s Guide to TNF Biology and to the Principles behind the Therapeutic Removal of Excess TNF in Disease. Neural plasticity. 2015;2015:358263.
- Tai LM, Ghura S, Koster KP, Liakaite V, Maienschein-Cline M, Kanabar P, et al. APOE-modulated Abeta-induced neuroinflammation in Alzheimer’s disease: current landscape, novel data, and future perspective. J Neurochem. 2015;133(4):465-88.
- Neurex symposium, Meeting on the roles of TNF in brain dysfunction and disease, http://www.neurex.org/?s=tnf+brain+dysfunction&x=0&y=02012 May 10-11, 2012; Basel, Switzerland.
- Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence. CNS Drugs. 2014;28(8):679-97.
- Begley S. In the Lab: Alzheimer’s researchers seethe over years of missteps after latest drug failure. STAT: reporting from the frontiers of health and medicine. https://www.statnews.com/2016/07/28/alzheimers-drug-failure/, July 28, 2016.
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