Rheumatoid arthritis and Alzheimer’s disease, what’s the connection?

It has recently been reported that a drug currently used to treat rheumatoid arthritis (RA) may also pack a punch in the fight against Alzheimer’s disease (AD). This discovery may be hailed by the media as a big step forward for AD research but what does it really mean?

To pick apart this discovery, we first need to delve into some background on Alzheimer’s itself:

Screen Shot 2016-08-08 at 20.47.27Much of what we know about Alzheimer’s disease in the human brain comes from postmortem studies. This means that most of our knowledge is skewed towards late stages of the disease. We know that, in these late stages, patient’s brains are severely shrunken and littered with clusters of abnormal proteins known as amyloid plaques and tau tangles. Many academics acknowledge that if we want to successfully treat AD it’s important that we understand what causes these proteins to misbehave in the first place. This is where scientists picked up on an important link between RA and AD.

Rheumatoid arthritis is an autoimmune disease which causes inflammation, pain and swelling in joints. Interestingly, alongside chronic inflammation, many RA sufferers also experience what is known as secondary amyloidosis resulting from deposition of amyloid protein fibrils. This form of amyloid starts life in the liver before being cut into smaller pieces and then deposited in other tissues – importantly this process appears to parallel the deposition of amyloid in the AD brain. Another important parallel between the two diseases is the presence of tumor necrosis factor (TNF) – a pro-inflammatory cytokine. Researchers believe that RA may be driven by TNF and it is also known that AD patients show elevated levels of TNF in their cerebrospinal fluid.

So, is it possible that TNF could play a causative role in both RA and AD and, if so, can modulation of TNF be used as a treatment for both diseases?

In a recent study Richard C.Chou from Dartmouth-Hitchcock Medical Centre collected medical records from over 8,000,000 US patients and his team began crunching numbers in the hope of answering these questions. They found that patients suffering from RA (over 40,000 patients) had a significantly increased risk of also developing AD. In fact, RA patients over the age of 65 were more than twice as likely to suffer from AD than non-sufferers (2.95% of RA patients also suffered from AD in comparison to 1.37% of non-RA patients). What was even more interesting was that patients treated with the RA drug etanercept (an anti-TNF agent) were significantly less likely to suffer from AD than other RA patients.

These results suggest that both RA and AD may share a common mechanism, perhaps linked by the actions of TNF? It also raises the possibility that anti-TNF therapies could have a future in the treatment of AD.

Although this work is just one more piece in the Alzheimer’s puzzle, the implications seem to suggest a role for inflammation and perhaps TNF in disease progression – something which has also been highlighted in previous studies. So, although (as is often the case) more research is needed, it does seem like we are making some significant headway in understudying and hopefully treating Alzheimer’s.

Post by: Sarah Fox




5 thoughts on “Rheumatoid arthritis and Alzheimer’s disease, what’s the connection?

  1. Tumor necrosis factor increases the risk of Alzheimer’s disease via the production of peroxynitrite. Peroxynitrite, through nitro-oxidative stress, inhibits the release and synthesis of neurotransmitters needed for short-term memory, sleep, mood, social recognition and alertness, inhibits the transport of glucose and reduces the flow of blood in the brain which can cause delusions, prevents the regeneration of neurons in the hippocampus, and leads to the death of neurons.

    It is only necessary to put a few essential steps together to understand Alzheimer’s disease:

    “TNF-induced PKC activation mediates ONOO- generation, which results in the oxidation and depletion of glutathione…”

    “Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

    “The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH [glutathione] levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI [mild cognitive impairment].

    Several peroxynitrite scavengers have already partially reversed Alzheimer’s disease in human clinical trials including eugenol in rosemary essential oil via aromatherapy (Jimbo, 2009) and ferulic acid, syringic acid, vanillic acid, p-coumaric acic, and maltol in Korean red ginseng and heat processed ginseng (Heo 2011 and 2012).

  2. This paper [1] is certainly an important confirmation of an idea that is probably game changing. To understand what is going on here we have to delve into the TNF literature, not just that of Alzheimer’s disease (AD). This outcome in rheumatoid arthritis patients is entirely consistent with the concepts contained in a 2015 review [2] on the roles of TNF in neurodegenerative diseases. TNF is astonishingly widespread in normal physiology as well as, in excess, in disease in such disparate groups and corals, fish, birds and mammals. The concept of etanercept being a useful treatment for Alzheimer’s disease has actually been around, and published, for ten years. It did not, as this recent article suggests, arise from the amyloid field, but from an open trial published in 2006 on 15 AD patients for six months [3]. The rationale was nothing to do with beta amyloid (although, as reviewed, high TNF has since been shown to be one of the inducers of this form of amyloid [4]). Instead, as described in Tobinick’s original AD text [3], the rationale of using etanercept was that excess brain TNF kills neurons. The concept, including of the route used to get this large molecule like etanercept to bypass the blood-brain barrier, has been discussed in detail a number of times since [5-7].

    The exciting thing about the Chou paper discussed in this blog is that it shows that simply reducing TNF levels is sufficient to influence the onset of AD. This is clearly compatible with smaller doses, given by Tobinick’s route so that very much more of it gets into the brain, compared to the negative outcome when was is given subcutaneously in the 2015 Southampton study [8], being useful in established disease. This publication is bound to give much traction to the approach of Tobinick and co-workers, perhaps sufficient, in what, despite years of patient trial failures, is still an amyloid-dominated AD research world, to be finally funded for a human random control trial.

    1. 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, in press.
    2. 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 Plast 2015, 2015:358263.
    3. Tobinick EL, Gross H, Weinberger A, Cohen H: TNF-alpha modulation for treatment of Alzheimer’s disease: A 6- month pilot study. Medscape General Medicine Neurology and Neurosurgery 2006, 8:25.
    4. Clark IA, Vissel B: Amyloid beta: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer’s disease. Br J Pharmacol 2015, 172:3714-3727.
    5. Tobinick E: Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs 2009, 23:713-725.
    6. Tobinick E: Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother 2010, 10:985-1002.
    7. Tobinick EL: Perispinal Delivery of CNS Drugs. CNS Drugs 2016, 30:469-480.
    8. Butchart J, Brook L, Hopkins V, Teeling J, Puntener U, Culliford D, Sharples R, Sharif S, McFarlane B, Raybould R, et al: Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, Phase 2 trial. Neurology 2015, 84:2161-2168.

  3. These results suggest that both RA and AD may share a common mechanism,

    yes a buildup of interstitial fluid that the lymphatic system doesn’t pick up
    in both cases drugs really are not very effective because the lymph capillaries are crushed and the cells are overloaded and osmosis doesn’t occur , so just like in cancer treatment the drugs just pass on by . Not to worry though pharma will sell you them even if they don’t work
    Mechanical solution in both cases….ALZ breakup blockage in neck…and if you have RA in your hands…..take a look at your elbows !!…


  4. Many drug compounds are unable to enter the CNS if, (pharmacokinetically speaking) they are administered outside of CNS (peripherally), i.e., orally, subcutaneously, intramuscularly, or intravenously.
    This is due a physiological “shield” consisting of specialized capillary beds known as the Blood-Brain-Barrier, the evolutionary purpose of which is to keep potential neurotoxins from entering the CNS. It also, however, prevents many potentially therapeutic compounds for Neurodegenerative/Neuropsychiatric/Neurotraumatic conditions from reaching the very physiological substrates (targets) necessary for them to exert their beneficial effects.
    It is for this reason that the very recently developed protocol known as the perispinal injection administration route of drug delivery is nothing short of a game changer in pharmacology, allowing for peripheral, non-invasive delivery of such compounds to penetrate the CNS.
    The area in which the injection is performed (known as vertebral venous plexus), is a bi-directional system; it can be conceptualized as an interface between the peripheral lymphatic system and the ventricular system in the CNS.
    A single injection of etanercept, for example, into the vertebral venous plexus followed by a maneuver (similar to a session in the popular relaxation device known as the inversion chair) called Trendelenburg positioning directs the compound through the choroid plexus and into the ventricles. Therefore, this injection, which is subcutaneous and performed peripherally, is non-invasive, most importantly, it has been shown to thwart the “first domino” in a plethora of Neurodegenerative, Neurotraumatic, and Neuropsychiatric Pathologies.

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