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Alzheimer hypothesis stuck in intellectual cul-de-sac

The size and growing magnitude of the dementia epidemic has forced a welcome decision by health ministers to name the disorder as Australia’s latest national health priority area. Yet for researchers searching…

Dementia has become Australia’s latest national health priority. John/Flickr

The size and growing magnitude of the dementia epidemic has forced a welcome decision by health ministers to name the disorder as Australia’s latest national health priority area.

Yet for researchers searching for a dementia cure, a recent large negative clinical trial based directly on the amyloid hypothesis of Alzheimer’s disease underlines the idea’s growing irrelevance and even negative influence.

A brief history

Alois Alzheimer described his famous case of Auguste D in 1906. This patient was a 50-year-old woman with complex psychiatric symptoms and memory loss. On autopsy, a dense distribution of deposits or plaques were found throughout her brain. These days we wouldn’t diagnose her with garden variety Alzheimer’s disease – but so started the long and complex saga that is this illness.

In the 1980s, several groups (one led by Australian professor Colin Masters) isolated the main protein in these “senile plaques” as fibrillar amyloid: long, twisted and insoluble proteins assumed to be the prime culprit in Alzheimer’s disease. For the next 20 years, hundreds of science papers were written about the toxic effect of fibrillar amyloid and how the build up of these molecules in the form of senile plaques was antecedent to dementia, and the basis for the accompanying neuronal loss. Remember that dementia is the clinical syndrome of progressive mental dysfunction that causes patients to present to their doctor.

Cracks in the hypothesis

In the last two decades, three inconvenient truths have emerged for the amyloid hypothesis. First, it’s now clear that about 30% of individuals with moderate to severe senile plaques at death were never demented in life. So the plaques (and their component fibrillary amyloid) don’t necessarily lead to dementia. It’s also now clear that the majority of people diagnosed with dementia have a mix of two pathologies in their brain – fibrillar plaques and vascular disease. And finally, that amyloid is a natural physiological protein in the brain, vital to synaptic function.

But during this time, some smart scientists came up with the idea of developing a vaccine against amyloid. The argument was that if the body could better eliminate it then the terrible mental deterioration experienced by those with dementia should halt, if not reverse.

First failed trial

Mice results were marvellous – in fact, we have since cured Alzheimer’s in mice many times over. But human studies have been spectacular failures. The first incarnation of the vaccine was based on active immunisation, relying on the body to raise antibodies to a foreign amyloid challenge. After 6% of participants developed severe brain inflammation, the trial was called off. In retrospect, this was perhaps unsurprising given amyloid is a physiological protein.

Researchers have cured Alzheimer’s in mice many times over. Kessa Ligerro

Just as troublesome was the observation that in those patients who mounted a strong immune response upon vaccination, autopsy showed there was indeed evidence of removal of senile plaques from their brain (hurray) – but their dementia progressed unabated (boo).

So, in living, breathing humans, the clinical disorder of dementia decouples from the disease state of fibrillar amyloid plaques. These results also raise a deeply troublesome issue for basic scientists and those in the drug business. Mice models of Alzheimer’s disease are only nominal, mere reflections of our theories; if the theory is weak then the model is worthless.

History repeated

The drug company Elan, which developed the original amyloid vaccine was taken over by Pfizer and Johnson & Johnson in 2008. The new team concluded that the problem didn’t lie with the amyloid hypothesis, but rather that a passive vaccine was needed.

Fast forward four years, a $1bn investment and a series of clinical trials of bapineuzumab involving 2400 patients. Last week, the results of Phase III trials were announced: no evidence of clinical efficacy on any cognitive or functional outcome (even after data mining), and all future trials of the drug halted.

These kinds of results should have triggered a profound reconsideration of the amyloid hypothesis. So is the field now finally moving on? Perhaps and perhaps not. Investors are running for the door (see these hard-hitting commentaries from Forbes, here and here), but the die-hards have thrown two counter-punches.

New orthodoxies

The first tenet of the new orthodoxy is that the pathological process starts 20 to 30 years before symptoms appear. While probably true, there are two fatal flaws with the argument’s extension – that we should be starting anti-amyloid therapy in our 40s and 50s.

The cross-section of the brain of an Alzheimer’s sufferer. AJ Cann

First, as now conceded, 30% of those with significant amyloid plaques (the overt disease) will never dement (the disorder), but die of other causes with intact mental function. So taking a potentially dangerous and expensive anti-amyloid drug for 20 to 30 years would prove futile in those who otherwise would never have developed the disease, and redundant in the one-in-three who do. What’s more, we need to ask again what exactly is the disease process of interest? There are now serious questions about whether fibrillar amyloid has a causal relationship with neuronal loss and related mental dysfunction. So any drug attempting to rid the brain of it is suspect.

The second new orthodox view rejects the assumption of the last 100 years that fibrillar amyloid is the villain. Rather, it considers that the amyloid you can’t see under the microscope is the real problem. Small ensembles (oligomeric) of soluble amyloid are thought to be toxic, not the twisted insoluble stuff first seen by Alois Alzheimer.

And what of that mass of research concluding that fibrillar amyloid was bad? That was based on barnyard concentrations of the stuff, the kind of non-physiological doses that would kill off anything. In fact, if we test amyloid at a more natural physiological range, it seems to help neuronal function.

In fact, one of the founders of the amyloid hypothesis has gone to the extent of speculating that fibrillar amyloid may be a good thing. That it may be the body’s way of locking away the harmful oligomeric amyloid in relatively innocuous plaques. What was once evil is now blessed, and the toxic culprit invisible, hard to measure and in an unknown dynamic relationship to “good” amyloid.

To consummate confusion in the area is the current fad of looking for “biomarkers” – biological tests to tell us the state of amyloid in the brain. The most fancy and expensive of these is PIB imaging, a molecular technique for visualizing plaques in the live brain. Several companies and research groups around the world are trying to champion it as a method of better diagnosing Alzheimer’s disease and monitoring treatment.

And what type of amyloid does it visualize? Fibrillar – the same type the new orthodoxy rejects as pathologically irrelevant.

Oligomeric amyloid may or may not turn out to be one of the causal factors behind dementia, but let us not repeat the same mistakes of the last 100 years. We must understand its physiological function, test it at realistic concentrations, and if vaccines against this form of the protein also fail, then the amyloid hypothesis should be buried once and for all.

After all, there’s nothing more destructive to the progress of medical science than an unfalsifiable belief.

Join the conversation

39 Comments sorted by

  1. Sherry Mayo
    Sherry Mayo is a Friend of The Conversation.

    logged in via Facebook

    Are there any strong competing hypotheses for Alzheimer's emerging? I was very tangentially involved in Alzheimer's research for a short time and was (as an outsider) struck by how mysterious and elusive the disease remained despite the long years of research on amyloid plaques. It would be rather sad if researchers had been barking up the wrong tree all this time.

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    1. Matthew Albrecht

      Postdoctoral Researcher at Curtin University

      In reply to Sherry Mayo

      As far as I'm aware (and I have still have to read the two papers linked in the article which I'll do now), people are now thinking that tauopathy is perhaps the more important pathology involved in AD, and the amyloid beta stuff occurs upstream of tau protein pathologies. So the amyloid beta fragments that come before the plaques may still be involved in the AD pathology but just not sufficient to cause the signs and symptoms and most likely by influence tau. (tau is a microtubule protein needed for intraneuronal transport)

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  2. John Q Citizen, Aussie

    Administrator

    As the son of a Dementia sufferer, and along with my sibling, battling a bureaucratic nightmare this & Alz brings to families. Really does the cause a lot of good when reports like these pop up and show us that as well as battling Local, State & Federal Govt duplication, NGO's who are really Empire builders of the highest order and some staff who should be removed for incompetence....Then the very people who should be advancing the treatment and developing new therapies blunder about & we are left with what exactly.
    Shame on the lot of you for your own designs and ego's, get your act together& do whats needed for the greater good...then again!

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    1. John Q Citizen, Aussie

      Administrator

      In reply to Matthew Albrecht

      Sorry Matthew you missed the point. I will assume you do not have a parent with dementia? The internal politicking is distracting the real issue. That you defend what you are doing is fine by me.

      My comments relate to real-time issues within the bureaucracy and what appears to be, in this article, a potential bun-fight or a percieved lack of direction for those in academic circles, tasked with "magically thinking up a cure" as you so boldly put it.

      That my initial comment has 4 red flags perhaps indicates the a very real gulf between sufferers, carers and academia? A fight for anorther perhaps.

      PS; Please refrain from cute comments "Just rock up to work one day and magically think up a cure?" You do yourself no favours!

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    2. Matthew Albrecht

      Postdoctoral Researcher at Curtin University

      In reply to John Q Citizen, Aussie

      John, so I can more appropriately deal with your comment, could you please separate out the bureaucratic issues from the scientific ones? You're conflating them at the moment and I don't know what your scientific issue is.
      Thanks.

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    3. George Fink

      Professorial Research Fellow

      In reply to John Q Citizen, Aussie

      John...your point is taken. It may not help to alleviate your frustration but neuroscientists are equally frustrated, and also have relatives and close friends with Alzheimer's Disease (AD) and other seemingly intractable neurological disorders such as Parkinson's disease and multiple sclerosis. Biomedicine has so far solved or at least produced effective treatments for diseases that might, on reflection, be regarded as low-hanging fruit...these include infections, most endocrine disorders (including…

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    4. Lucy Mae Mirren

      logged in via Facebook

      In reply to Matthew Albrecht

      I’m with you, John.
      Michael, George … all the science in the world is of little use to anyone if we cannot get the “human” aspect of aged care right. And at present, in Australia, we have not – largely because the technocrat and the social scientist have gained the upperhand over good old-fashioned listening and tender loving care.

      John, may I commend to you the Melbourne advocacy group, agedcarecrisis.com. These people came together out of the unhappy experiences of their own elderly parents in care and they have spent a decade advocating, on the personal level and political level, for a better deal for the elderly in care. They are a fount of wisdom in dealing with the bureaucracy and, if nothing else, you will discover that you are far from alone in your “bureaucratic nightmare”.

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    5. John Q Citizen, Aussie

      Administrator

      In reply to Matthew Albrecht

      Matthew I am not an academic, I am as you see form the post above at the sharp end of Dementia and in particular a parent with FTD. I too have a persuasive turn of phrase and a grasp of large poly-sylalbic verbage :)

      Stay away from me alright, I don't like it when academics argue the toss, amongst themselves. It has shown itself to amongst other things to include posturing for funds and other unpleasentness which distracts from why we are here and our roles in life. I do hope you understand, now go away and do your job and let others do theirs!

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    6. John Q Citizen, Aussie

      Administrator

      In reply to George Fink

      Thank you George. The on-going battle for funding, for a 'profile' if one puts it bluntly is sad and disappointing. I understand the frustrations of the scientific community and that down the track the Pharm industry may well put patents on their' discoveries' and then charge large sums of money to recoup their 'investments'

      All carers ask is for direction, to be honest, pulling in the same direction.

      If the message gets lost internally, then the message externally becomes blurred and confused, folks get annoyed and from a philanthropic perspective the folks with the money go elsewhere, less politicking and ego. How do I know? a good friend of mine, his wife worked for a major bank specifically in the Philanthropy Division and she told me a few things over dinner one night....sad isn't it.

      We all hope and pray for a cure or steps towards a cure.

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    7. John Q Citizen, Aussie

      Administrator

      In reply to Lucy Mae Mirren

      Hi Lucy, thank you for the heads up on the Advocacy Group in Melbourne, run on the smell of an oily rag.

      These groups are out there and need help. Help comes from letting others know of their existence, simplistic but thats how things change. That the Clt Govt has set aside funding for these issues is one step further. As it stands there needs to be a bigger lobby group(s) to push this further

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  3. Keith Thomas

    Retired

    Thank you very much, Michael, for the best popular-level update I have ever read on our understanding of Alzheimer's and the research on pharmacological approaches to treating the disease. I can appreciate John's position to some extent (though not so much the unpleasant way he chose - behind a pseudonym - to raise that position). The fact is that whenever there is big money around, there is politics and there are self-serving special interests. (I am not associating you with this in any way, Michael…

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    1. George Fink

      Professorial Research Fellow

      In reply to Keith Thomas

      Keith....Re Life style and AD....Numerous studies have been and are still being carried by Labs including a major prospective study in Australia, led by Prof Colin Masters of the Mental Health Research Institute, UniMelb....

      Re your comment about "no Nobel prizes to be awarded", here, as an example, is a list of the Prizes previously awarded in recognition of the discovery of vitamins which lead to major positive lifestyle changes:

      Nobel Prize in Physiology or Medicine
      Discovery of Vitamins…

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    2. George Fink

      Professorial Research Fellow

      In reply to Keith Thomas

      Oh no...don't do that....your Lifestyle point was excellent...thought I should just remind ourselves re vitamins and other possible unknowns....AD has gone through several lifestyle iterations....but so far perhaps only regular exercise (good) and possibly cholesterol (? ? bad) might play a role. In the 1980 s aluminium was implicated (so folks stopped using aluminium pans...But that proved to be incorrect (data on aluminium flawed).
      Main thing is to avoid if possible being born with the AD gene (rare) and /or apolipoprotein epsilon 4 isoform (APOEe4) which is often associated with sporadic AD

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  4. Tom Hennessy

    Retired

    They've shown feeding meat to a herbivore causes Alzheimer's.

    "The nutritional contribution to bovine spongiform encephalopathy"
    http://www.ncbi.nlm.nih.gov/pubmed/2038456
    "Evidence that changes in source of protein from plant to animal alters the membrane fatty acid composition of ruminant tissue is presented by comparing zoo giraffe with the same species from their natural habitat."
    "Changes in animals feeds would have depleted cattle tissue membranes and made them susceptible to bovine spongiform encephalopathy"

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  5. Michael Valenzuela

    Associate Professor & Leader of Regenerative Neuroscience Group, Brain & Mind Research Institute at University of Sydney

    Hi Keith

    Thank you for your comments. In response to some of your questions (and that of some others), what I tried to outline in my opinion piece was the current status of the amyloid hypothesis of Alzheimer's disease (AD). There are several other hypotheses for the basis of AD, including tau-pathology, yet none I would describe as strong theories.

    If you are after a more complete picture about different AD theories, and more importantly, accurate information about how to best prevent the onset of dementia and keep your brain healthy, I naturally recommend my book, 'Maintain Your Brain'.

    Your question about lifestyle factors is very good. In fact, this is one of the main themes my research group is targeting. There is increasing evidence for a positive role for cognitive lifestyle, physical exercise and control of high blood pressure. You can learn more about my group's research at www.rng.org.au.

    Thanks again

    Michael

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    1. Lisa Hodgson

      Director

      In reply to Michael Valenzuela

      Hi Michael,

      would you not consider the Aluminium (accumulated toxin) hypothesis strong? Even if you consider it weak is it not worthy of further investigation? Given that Al is *consumed in a number of ways e.g. cooking, drinking water, food, vaccinations etc. Especially given that many animal studies demonstrate neurotoxic effects. Rather than searching for a cure or a vaccine for AD should we be more interested in the cause? We didn't find a cure for lung cancer yet the main cause is being dealt…

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    2. Keith Thomas

      Retired

      In reply to Lisa Hodgson

      I support Lisa's question. John referred to 'politics' and I have read on the web that the aluminium industry claimed that the initial association between aluminium and Alzheimer's was due to brain samples being contaminated by the aluminium foil in which they were stored.

      Leaving aside the correctness of this claim, it shows clearly how politics intervenes to the detriment of rational consideration of the serious issues.

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  6. Rhonda Nay

    logged in via LinkedIn

    I see two very different issues: Michael 's paper which. Is related to cause and Keith 's concerns which I think are really about care and the great difficulty people living with dementia experience. Thinking outside the current paradigms is essential for both but finding the cause will not help Keith with his frustration. Fortunately dementia has finally Ben made a national priority and we can only hope that means some of the barriers you face can be reduced. Immediate assistance could be available through Alzheimer's Australia and or feel free to call our dementia centre and/ or google TIME for dementia
    Hope this helps
    Rhonda

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  7. Danielle James

    retired

    Of course, there are other forms of dementia. Is there a common pathology between different types?

    My husband has fronto-temporal lobe dementia which causes him to become extremely violent. He is in a high-care facility and given a drug used for schitzophrenia to control these episodes - episodes which are very frequent.

    An odd thing is that he can be absolutely coherent for the first five minutes when talking to him, then launches into full dementia with hallucinations and delusions. It is almost as if he has a five-minute reserve of rational thought.

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    1. Keith Thomas

      Retired

      In reply to Danielle James

      That's a poignant story, Danielle. My own mother, at 95, is quite different. Always mild - too mild, sadly. Some days she does not recognise me and has no interest in leaving her room. Yet on other days she will be able to reflect to the extent that she can say "I am having a good day today, so let's go out for a drive". And she does indeed have a good day.

      Still another care problem was described in the New York Times earlier this week: caring for dementia patients who had been violent, deceitful, abusive and unpleasant before they showed symptoms and even well into the disease behave true to form.

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    2. Danielle James

      retired

      In reply to Keith Thomas

      Keith,

      Did your mother at any stage feel she was getting dementia? It also sounds like depression. I believe that dementia and depression can be confused.

      In the "earlier" stage (about 18 months ago), my husband would come to me in a panic and say that he felt he didn't exist. He had a little insight. He observed at one stage, that he felt "this was the end", he said his mind had large holes in it, but there was no pain nor other sensation. At this period he was also having halucinations and delusions and would often not know what a common item was for, nor do a very simple task.

      You made mention of an article in the NY Times. Indeed, my husband was an extremely difficult man to live with; so much so, that as his dementia/violence got worse, my daughter observed that "it was just more of the same."

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    3. Danielle James

      retired

      In reply to Danielle James

      One thing that did seem to help my husband early on, were vit B12 injections, which I asked the doctor to administer. Although my husband was not an alcoholic, I had seen the results of B12 injections on those suffering dts, and it seemed to be effective.

      It was worth a try, and certainly my husband's hallucinations abated for a while. This, of course, could have been merely coincidental.

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    4. Keith Thomas

      Retired

      In reply to Danielle James

      I don't think so. She has kept her sense of humour - not only to laugh at things (entirely appropriately), but also to crack her own little jokes (which were of her own making and were genuinely humorous). Not often, by any means, but frequently enough to give me hope. However, doctors have tested her and assured me she has dementia. She has also been diagnosed with depression and has a prescription to deal with that.

      Dementia takes many forms and treatment, care and mitigation must also meet…

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    5. Tom Hennessy

      Retired

      In reply to Danielle James

      Vacular dementia, alright sitting down , but as soon as they stand up , lack of blood flow , .

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    6. John Q Citizen, Aussie

      Administrator

      In reply to Danielle James

      Hi Danielle, I sympathise with you, i have a parent with FTD, its a terrible diagnosis, after finally getting the dx for Dementia.. There is and FTD Support Group in Melbourne ((St George's, Kew) DBMAS have a large input into things as well. They meet once a month. So if that helps!

      Our parent has recently started abusing the rest of the family, and as someone who is an ex-cop it startled me. I thought I was used to verbal abuse, one never is especially when its a loved one.

      The lack of understanding, from many doesn't help. The 'two faces' of the FTD sufferer never cease to amze me and I've seen a lot. I wish you all the very best, as lame as that sounds.

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    7. Danielle James

      retired

      In reply to John Q Citizen, Aussie

      John Q Citizen,

      Thank you very much for you kind words and information.

      I'm increasingly hearing about diagnoses of FTD. I had thought it was a less common form of dementia. In one case, a woman has had a heavy door and locks installed on entry to a small room, where she has been advised to take refuge should her husband become violent.

      A counsellor from Alzheimers Australia warned me at the outset that I would be in for a very challenging time, and that deaths have have been caused by the violence of FTD sufferers. The problem is that there is absolutely no warning of an attack - it comes out of nowhere.

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    8. John Q Citizen, Aussie

      Administrator

      In reply to Danielle James

      Danielle, DBMAS are a 24 hour Counselling Line. 1800 699 799.

      http://dbmas.org.au/

      I appreciate your spouse is in High Care, but sometimes it helps to have a voice to talk to to as my late Gran used to say " to get it off your chest' with someone who really knows.

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  8. Tom Hennessy

    Retired

    We all seem to have forgotten the all familiar , iron hypothesis of Alzheimer's. I kind of find it interesting noone has mentioned it. It must be due to ignorance. The tau amyloid is there to protect from the iron accumulation. By targeting amyloid for removal without also targeting the metal accumulation would be akin to 'picking at a scab'.
    "Reduction of iron-regulated amyloid precursor protein and beta-amyloid peptide by (-)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer's disease.".
    One must target the underlying cause of the amyloid buildup , iron due to ischemia , lack of blood flow , which has never been removed.
    "Getting the iron out: Phlebotomy for Alzheimer’s disease?"
    "Ferric cycle activity and Alzheimer disease"

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    1. Tom Hennessy

      Retired

      In reply to Tom Hennessy

      When blood flow slows , venous stasis , happens.
      "The role of iron neurotoxicity in ischemic stroke."
      "Redox-active iron mediates amyloid-β toxicity"

      It is the same concept as venous stasis , low blood flow , which leads to , "Hemosiderin staining","caused by the degradation of red blood cells
      within the interstitial spaces" , the same inside the skull , as per Zamboni and iron buildup in Multiple Sclerosis.
      "Anomalous venous blood flow and iron deposition in multiple sclerosis".

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  9. Cris Kerr

    Volunteer Advocate for the value of Patient Testimony & Sustaining our Public Healthcare Systems

    In the interim... that is; long before 'a cure is discovered, patented, and sold to the dementia market' and hopefully long before approval is granted to a Gold Coast university to trial the latest headline (an invasive treatment involving anti-inflammatory injections into spinal fluid)... those interested in slowing immune system disease progression might be interested in reading my submission to Australia's Strategic Review of National Health & Medical Research 2012:

    Submission No. 296 - Cris…

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  10. Cris Kerr

    Volunteer Advocate for the value of Patient Testimony & Sustaining our Public Healthcare Systems

    In the interim... that is; long before 'a cure is discovered, patented, and sold
    to the dementia market' and hopefully long before approval is granted to a
    Gold Coast university to trial the latest headline (an invasive treatment
    involving anti-inflammatory injections into spinal fluid)... those interested in
    slowing immune system disease progression might be interested in reading
    my submission to Australia's Strategic Review of National Health & Medical
    Research 2012:

    Submission No…

    Read more
  11. Lane Simonian

    History Instructor

    The cause of Alzheimer's disease is a toxin called peroxynitrite. Since the mid-1990s it has been known that peroxynitrite-mediated damage is widespread in Alzheimer's disease and researchers have added to that knowledge through the years. Peroxynitrites oxidize (damage) g protein-coupled receptors that affect short-term memory (acetycholine muscarinic), mood (serotonin and opioid), sleep (melatonin), neuron regeneration (via beta-adrenergic receptors), alertness (dopamine), social recognition…

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    1. Rhonda Nay

      Emeritus Professor La Trobe University at La Trobe University

      In reply to Lane Simonian

      That's good - we can all go home and stop researching because the problem is solved? Or maybe it just means all the research dollars can go into better care for currently diagnosed people?

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    2. Lane Simonian

      History Instructor

      In reply to Rhonda Nay

      Both actually. Aromatherapy has been fruitfully used in various facilities to help patients with Alzheimer's disease and their family members in both the United States and Australia. For the United States, the two largest groups of "memory care homes" using aromatherapy are Ecumen in Minnesota and Potomac Homes in New Jersey. The major Australian study involved essential oils delivered via massage. I will copy the results:

      Kilstoff K, Chenoweth L. International Journal of Nursing Practice…

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