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Alzheimer's Disease

Microbial Alzheimer’s: The Arguing Continues

The Journal of Alzheimer’s Disease has published an editorial, signed by thirty-one researchers from institutions across several continents, calling on a re-evaluation of the disease’s origins:

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain. . .

They’re referring specifically to HSV1, chlamydia, and some spirochete bacteria species, all of which have been found (in one study or another) to be elevated in the brain tissue of AD patients. They reference the (not very strong) studies suggesting fungal infection, but those aren’t really part of their argument, most of which concerns evidence for HSV1. They propose that these infectious agents are latent in brain tissue until reactivation by aging or stress, and that the pathology of Alzheimer’s is due to their actions and to the inflammatory response to them.

This is not a crazy idea (nor is it a new one, for that matter). It’s certainly not in the mainstream of Alzheimer’s research, as many in the field have said when called on for comment over the last few days, but it’s not the work of a bunch of cranks, either. The editorial ends up by saying “We propose that further research on the role of infectious agents in AD causation, including prospective trials of antimicrobial therapy, is now justified”. And that’s both the good part and the bad one about this area. The good part, which is indeed very good, is that this is a testable hypothesis. There are therapies for all the infectious agents mentioned, and if they really are the cause of Alzheimer’s, then you’d think that giving them to an elderly cohort would lead to a notable decrease in AD compared to the general population.

The bad part is that clinicians have been reluctant to dose these patients with years of antibiotics or antivirals for what may be no good reason. You’d want to be sure that whatever drugs you’re giving can achieve sufficient levels in the brain as well, which could be a challenge – if you have to go to the more direct methods of dosing for the CNS, that’s going to make getting a clinical trial off the ground nearly impossible. This editorial, in the end, is saying that it’s time to go ahead and try this, though, that the existing AD therapies have by now had enough trouble delivering meaningful results that other hypotheses are looking more valuable than they might have twenty-five years ago.

It’ll still be a tough sell. Ideally, you’re going to want to find older patients who (as far as can be told) have nothing wrong with them, and sign them up for what could well be years of anti-infectious drug dosing. You’re going to have to find someone who’s willing to pay for this, someone who’s willing to sign off on it as an acceptable clinical trial, and round up enough patients who are willing, after informed consent, to give it a try. None of those are going to be trivial. But overall, I tend to think that these authors are right – not that Alzheimer’s is caused by infectious organisms (I have no idea if it is or not). But I think that they’re right that it’s time to find out.

73 comments on “Microbial Alzheimer’s: The Arguing Continues”

  1. Bunsen Honeydew says:

    Hear, hear! I have to agree. I’m no AD expert, but as a synthetic organic chemist, I have been keeping an eye on AD research for years. It has definitely been a long, sad story. I have had significant conversations with friends who are experts in enzyme kinetics and they passionately argue that many of the results we now have about beta-amyloid are totally misunderstood.
    And let’s not forget that the definition of insanity is doing the same thing over and over and expecting a different result. I think we have reached that point with AD. Let’s try something different. It should be plausible, which this seems to be, but definitely a new angle.

  2. steve says:

    You would think that a simple test would be to look at antibody titers in people with early stage Alzheimer’s. If HSV1 (or some other infection) is the causative agent then they should have elevated antibody titers compared to the rest of the population. Has anyone tried this before dosing patients with lots of antibiotics or antivirals?

  3. Me says:

    As always with AD, a lot of will, a lot of good science, and a lot of tantalizing clinical data with hints:-

    1. Mike C says:

      “The primary clinical outcomes are unequivocally negative”

  4. luysii says:

    Given the nearly nonexistent therapeutic results so far, all approaches to Alzheimer’s however far out should be at least considered. I do have a sinking feeling about an infectious cause, given the years of searching for infectious causes of MS, with finding after finding followed by lack of replication after lack of replication.

    If you’re willing to stretch your mind a bit. Here are two papers pointing to Alzheimer’s disease being a problem in physics rather than chemistry.

    1. Edgar says:

      There’s pretty good evidence linking EBV &/or other herpes viruses as well as HERVs to MS. See for example:
      Anti-Epstein-Barr Virus Antibodies as Serological Markers of Multiple Sclerosis: A Prospective Study Among United States Military Personnel,” KL Munger, LI Levin, KI Falk, Alberto Ascherio, Multiple Sclerosis Journal, October, 2011

  5. Anon says:

    Breaking news: Alzheimer’s disease is caused by death, as the two are correlated.

    In other news, old age is caused by HSV1.

    And science is rapidly going downhill.

    1. Anon says:

      … though I suppose if all 31 researchers get funding to test the idea, one or two of them will get a significant positive result with a p-value less than 0.05. So that’s good.

  6. mardukof babylon says:

    A lot of senior folks already take antibiotics for other causes.
    Perhaps a statistical analysis with a large enough data set would help.

    If we see that in people prescribed any antifungals for other reasons Alzhiemers is less prevalent then we have to update the odds.

    My guess would be that a national health service like in the UK will have that kind of data set.

  7. Ash (Wavefunction) says:

    Perhaps Yale’s Laura Manuelidis will have the last laugh after all?

    1. Mark Thorson says:

      I was initially deeply skeptical of the prion hypothesis, but eventually gave in. I’m glad somebody never gave up her skepticism. It wouldn’t take a lot to win me back to the skeptic camp — when you think about it objectively, the idea of a protein that catalyzes its own formation is pretty radical. A viral explanation is much more conservative.

      1. milkshake says:

        I was friend with a postdoc in Weissmann group at Scripps Florida, working on prions. He found clues that prions, while toxic on their own, were associated with co-infection with RNA viruses, and this in his opinion would explain existence of numerous prions strain better than multiple types of misfolding or glycation of the same amyloid protein (giving rise to different strains). He argued the animal models they were using for prion strain research were prone to generating artifacts, and plausibly important factors like viral transmission were not being accounted for. But his contrarian views did not endear him to his boss and he was pushed out.

        1. milkshake says:

          my bad, I take it back I just realized he was working on prions, not on Alzheimer. Sorry.

  8. JAB says:

    All well & good, except that we don’t have any very good drugs for HSV-1 (or -2). Acyclovir and prodrugs of acyclovir, and they are not very potent, have side effects, and resistance develops in extended treatment.

  9. Lane Simonian says:

    I know some people here are frustrated with me, but I am frustrated with nearly everybody else so we are even.

    The main problem here is not that chronic virus and bacterial infections may cause Alzheimer’s disease; the problem is that many other factors can cause Alzheimer’s disease as well. Researchers can find examples of viruses, bacteria, and fungi in people’s brains and conclude that this is “the” cause of Alzheimer’s disease. Other people can find no viruses, bacteria, and fungi in people’s brain and conclude this is not “the” cause of Alzheimer’s disease. Both are wrong, as there is not a “the” cause of Alzheimer’s disease.

    I will repeat again, Alzheimer’s disease is not caused by amyloid oligomers or plaques or by hyperphosphorylated tau (although nitrated tau or permanently hyperphosphorylated tau can inhibit neurotransmissions) but by oxidative stress. Anything that increases oxidative stress (bacteria viruses, fungi, high glucose levels, too many carbohydrates, high salt intake, high fructose corn syrup, psychological or physical stress, air pollutants, various pesticides and herbicides, mercury, aluminium fluoride, various genes and genetic mutations, etc.) increase the risk for Alzheimer’s disease. And certain antioxidants which reduce oxidative damage can be used to either slow down the progression of Alzheimer’s disease or partially reverse it (keep an eye on 12 week results for ANAVEX 2-73 this weekend). This includes certain antibiotics such as minocycline. But more effectively it includes THC, cannabidiol, and terpenes in medicinal marijuana, eugenol in various essential oils via aromatherapy, and syringic acid, ferulic acid, vanillin, maltol, and p-coumaric acid in heat processed ginseng.

    1. Anon says:

      Lane, as one of those who have consistently mocked and argued with you (more due to your biased approach to science rather than your theories), I actually agree with you that oxidative stress is probably the single common cause of AD, which may be induced by many different factors, *including* amyloid and/or tau. But then so does oxidative stress also cause arthritis and many other ailments. So that leads to the question: So what? What can we do about it?

      1. Lane Simonian says:

        Maybe then it is not so much the message, but how doggedly and without skepticism I present it. That comes from the fact that I am not heavily trained in the sciences which is both a curse (not being able to conduct experiments myself, for instance) and a benefit (being able to consider alternative explanations outside of the mainstream).

        Many diseases are the result of oxidative stress and/or inflammation. Indeed lipid peroxidation is one of the triggers for inflammation.

        Here is why one should care: if oxidative stress is a common element to many of the remaining poorly treated or untreatable disease then finding the most effective antioxidants may have applications for at least some and perhaps many of these diseases. Not all antioxidants are equally effective so that becomes the task of a biochemist to find the ones that are the most effective or which can be altered to make them more effective.

        1. Me says:

          quote: ‘(being able to consider alternative explanations outside of the mainstream’

          I think you’d be surprised how irrelevant that statement is if you hung around enough scientists for long enough. Your first comment, however, is a serious issue, since you can’t tell good science from bad. Plenty of journals exist to take fees off of people who get papers professionally written to help them hawk their snake-oil to unsuspecting punters.

        2. Anon says:

          Indeed, presenting with or without self-skepticism makes all the difference between a serious, credible scientist, and a snake-oil salesman. The goal of science is only to get to the truth, and for that, one *must* show that they are keen and willing to be proven wrong. Humility is everything in science.

          Meanwhile, my guess is that oxidative stress, whilst directly “causing” AD and many other ailments, is really a last-ditch attempt by the cell to save itself from something else as the mitochondria work overtime to restore homeostasis. So to stop oxidative stress, one must be prepared to stop the cell trying to save itself, which may cause the cell to die anyway. But evolution is pretty smart and oxidative stress certainly hasn’t evolved without the benefits outweighing the costs and risks.

        3. Guppy says:

          The oxidative-damage hypothesis gets dragged out for just about every enduring medical mystery — I even remember some folks seriously discussing it as a cause of AIDS way back when, even though it made no freaking sense given the epidemiology.
          Still, if people keep dragging it out, someone is eventually bound to be right.

    2. Emjeff says:

      So, you’re saying that the cause of AD is living….

  10. flem says:

    Isn’t amantadine, an anti-viral, used to treat parkinsons? Has anyone tried this drug on AD patients?

    1. Design Monkey says:

      Memantine (which is the same thing as amantadine, with two methyls stuck on) is being used for AD. Also amantadine isn’t universal miracle antiviral, even if fifty years ago people believed so, and legends like that are still floating around.

  11. Lane Simonian says:

    I remember once trying to set up a talk at the university through a pre-med organization. After I mentioned the word aromatherapy, they said they don’t sponsor talks on pseudoscience. My response was tell me how the ability of eugenol to donate hydrogen atoms to scavenge peroxynitrite is pseudoscience (ONOO- + 2H+ + 2e-= H20 + NO2-). But the student had already determined the truth before they had considered the mechanism. That is not much humility.

    I probably stated it unartfully–I should have said my apparent lack of skepticism. I understand the problems with studies that are small, lack a placebo and that are not double-blinded. The difference is I don’t believe therefore the results of the study are necessarily incorrect. The tendency, though, is to throw the baby out with the bath water.

    I have enough scientific ability to understand the mechanism behind the result and therefore I don’t automatically toss out the results based on the belief this or that plant compound should not work because it is snake oil.

    And yes, oxidative stress is often a way for a cell to save itself (and amyloid plaques are a way for a cell to try to save itself against hydrogen peroxide), but sometimes the damage done is worse than what it is trying to protect against.

    And perhaps most importantly of all, the damage done to the brain by oxidation and nitration can be partially reversed by certain antioxidants.

    1. Anon says:

      Certainly there are many (especially young) scientists that could do with a lesson in humility. Most scientists get the chance to learn that lesson with experience in due course. I’ve been there. 🙂

    2. Mike C says:

      Just how much eugenol does one have to smell for it to have a measurable effect on peroxynitrite or other ROS in the brain?

      1. Lane Simonian says:

        For my mother, it was a few sniffs of a few essential oils high in eugenol (clove, bay laurel, and rosemary) for a few seconds each morning under each nostril. She recognized her home again (once she said we are almost home before getting to the driveway), she stopped having delusions, her repetitive memory improved (reciting the alphabet, counting numbers, completing simple phrases), became better at recognizing objects (asking if it was sugar in a salt shaker, identifying a flower as a rose), had a better sense of time (after a month of aromatherapy she asked why have you been giving this to me every day for a month), had slightly better short-term memory related to place (remembering she had gone to the park, for instance), and was much more alert and aware. She was not noticeably more lucid and recently I found that lucid thought likely occurs in a different part of the brain (the anterior prefrontal cortex and not the hippocampus) so this makes sense as the molecules behind smell almost directly enter the hippocampus.

        Here are some titles that don’t answer your question but explain why eugenol potentially is useful for the treatment of Alzheimer’s disease (although it can also increase anxiety in some people via the activation of the sympathetic nervous system; one study tied this to the past use of clove in dental operations but it is likely more complicated than that).

        Effects of Eugenol on the Central Nervous System: Its Possible Application to Treatment of Alzheimers Disease, Depression, and Parkinsons Disease

        In Vitro Activity of the Essential Oil of Cinnamomum zeylanicum and Eugenol in Peroxynitrite-Induced Oxidative Processes

        Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures.

        1. JAB says:

          I used to be a huge skeptic of aromatherapy, and still have major reservations, but there are some increasing reports of possible mechanisms that may underlie what aromatherapists might observe. Most of what we are talking about in the field of aroma are monoterpenes, the pleasant (or not so pleasant) natural products which act on many of the bazillion olfactory GPCRs in the nose and nearby areas. Those receptors are mediators of perceptions of food, and there is an obvious psychological element there. BUT, some of these monoterpenes, and I would not pick eugenol as a particular example, have effects on other receptor systems – the best established example is the menthol receptor TRPM8, whose physiologic function is to sense cold temperatures. There are hundreds of monoterpenes and other not very drug-like molecules and some have been found to do interesting receptor biology. Connecting that to medical utility is a very long stretch but it offers the possibility of understanding some of what aromatherapy claims.

          1. Lane Simonian says:

            Very good observations. Terpenes are hydrogen donors. Much of the damage to transport systems, enzymes, and receptors (especially g protein-coupled receptors affecting smell, mood, short-term memory, sleep, mood, and alertness) are do to either oxidation or nitration. Hydrogen donation helps to reverse oxidation and reduce peroxynitrite. One of the products of that scavenging is water which is a putative de-nitrating agent.

            On another site, I had someone who strongly advocated from experience for the use of medicinal marijuana to treat Alzheimer’s disease but said the idea that aromatherapy could be used to treat the disease was ridiculous. I found that interesting because most people would find each either equally far-fetched or each equally plausible. But as it turns out, cannabis not only includes THC and cannabidiols which are peroxynitrite scavengers it also includes a number of terpenes that are peroxynitrite scavengers and the combined effects with other essential oils containing terpenes via aromatherapy is elusively promising.

            “As we know, science has identified and characterized the molecular structure of around 20,000 terpenes, which makes it the largest category of plant chemicals. These aromatic compounds are found in the essential oils of plants and flowers, and plenty of studies have been done on their effects.
            Of the 20,000 identified terpenes, there have been more than 120 found in cannabis. Only a few of them appear in high concentrations, but they have been found to have a number of benefits…Terpenes could also aid in Alzheimer’s treatment with cannabidiol (CBD). Linalool, which is prominent in lavender, helps counter stress and anxiety. Limonene is commonly used in aromatherapy to improve mood, and pinene is known to promote alertness and memory retention. Combining these terpenoids with a CBD-rich extract may help treat the wide-ranging effects of Alzheimer’s disease.”

            I am not always right, but I like to make people think about the science of Alzheimer’s disease and its treatment in a different way. To maintain a certain amount of doubt and skepticism is more than fine, as long as the mind does not completely close to alternative explanations such that name calling becomes a substitute for discussion.

  12. Javaslinger says:

    Lane, if your serious about any of this, why don’t you get trained in science? A nice chemistry degree perhaps?

    1. Anon says:

      A science degree per se won’t help, but the experience of doing real experiments to test hypotheses is invaluable.

      1. Lane Simonian says:

        Either that or raise over hundred thousand dollars for a qualified institution/organization to do the clinical trial for me. I can do the protocol, it is the cognitive exams and medical tests that I am incapable or running and analyzing. I am not a good fundraiser either but I would rather put this into fully competent hands if I can.

  13. johnnyboy says:

    I’ve read the editorial in question. It’s certainly a mish-mash of ideas, with unjustified leaps of logic and often contradictory statements – about what you’d expect from an editorial signed by 30+ academics from different institutions. That said, it’s certainly not a stupid proposition to want to test antimicrobials as AD prophylaxis, and I don’t think it would be that hard to fund and recruit enough people for a prospective trial of anti-Chlamydia or anti-spirochete drugs (it wouldn’t necessarily have to be constant treatment for years, it could easily be repeated short treatment periods to keep the bugs in check, for instance). But for HSV1, forget it. If it indeed has a role in AD, you’re gonna need a hell of a better drug than acyclovir to make a dent in it.

  14. anon says:

    … or a vaccine?

    Too bad there was no money to develop it.

  15. luysii says:

    Edgar: Yes elevated antibodies to a variety of viruses have been found, but this just appears to be heightened responsiveness of the immune system. Usually studies have looked at a single virus at a time finding elevated titers. Have any studies looked at a bunch of viruses in the same individual?

    We know the immune system is reacting to something in MS. Two very recent papers are finding out just what the inciting antigens actually are (one is anoctamin2, not a viral protein) and a way to specifically inhibit immune responses to a particular antigen without clobbering the whole immune system. Very exciting and hopeful stuff — for details please see

  16. blunderbuss says:

    “The amount of knowledge on any subject such as this can be considered as being in inverse proportion to the number of different treatments suggested and tried for it.” – Charles W. Mayo 1932

  17. Nick K says:

    Has anyone looked at trying anti-inflammatories in AD? Apologies in advance if this is a stupid question.

    1. Olden Tired says:

      I recall a news splash a long time ago about a retrospective study where a cohort of ibuprofen eaters had about 20% less AD than a matched cohort not using NSAIDS. Can’t remember any more details and it is time for me to go to bed.

    2. Lane Simonian says:

      Nonsteroidal anti-inflammatory drugs may reduce the risk of Alzheimer’s disease but they do not appear to be effective in the treatment of the disease.

    3. me says:

      There was also a trial with a powerful anti-TNF antibody (Enbrel). Did a phase 3 with AD. Don’t think they got anywhere with that either.

      1. Penny says:

        There was a Phase II with etanercept – pretty sure not a Phase III. Some still think the data is viable – another trial is underway led by Clive Holmes with funding from Alz Drug Discovery Foundation and others.

        1. Lane Simonian says:

          More on the earlier results of the study with Enbrel.

  18. steve says:

    The problem with the oxidative stress theory is that it is too general. Oxidative stress is a fact of life for every eukaryotic organism. If oxidative stress plays a major role in Alzheimer’s then the question is why as it is a symptom, not a cause. To say that everything causes oxidative stress is to ignore the fact that some people get Alzheimer’s and others do not. The oldest man in the world was recently identified as a survivor of Auschwitz and he is perfectly sensible at the age of 112. I’m sure he has encountered a lot of oxidative stress in his life, coming out of Auschwitz weighing 84 pounds, but he did not develop Alzheimer’s. Single-cell organisms that engulfed mitochondria and began oxidative phosphorylation pathways developed a number of ways of dealing with oxidative stress millions of years before humans evolved. If that is a central mediator of Alzheimer’s pathogenesis then it needs to be explained why it is manifested in the brain and not elsewhere (lots of tissues are subject to oxidative stress, it’s a central) and why it occurs in some people and not others. If you really want to pursue the hypothesis, a simple test would be to look at markers of oxidative stress in blood of patients such as isoprostanes, malondialdehyde, nitrotyrosine, etc. Still, it would only show that they have elevated levels of oxidative damage, not why.

  19. Lane Simonian says:

    This is one of the more intelligent critiques of the oxidative stress hypothesis of Alzheimer’s disease that I have seen, but most of the questions posed are not insurmountable.

    First of all it is the balance between oxidative stress and antioxidant defenses that are the critical element. There are a number of examples: people with Down syndrome have high levels of myo-inositol in their brain (a precursor to the formation of peroxynitrite) and almost all of them have plaques and tangles in their brain by the age 40, but not all people with Down syndrome go onto to develop Alzheimer’s disease. The main reason is that people with Down syndrome have high levels of hydrogen sulfide which is a peroxynitrite scavenger. People with gout are less likely to develop Alzheimer’s disease because they have high levels of uric acid and uric acid is a peroxynitrite scavenger. Uric acid and hydrogen sulfide cause all sorts of other damage, but they are protective against Alzheimer’s disease.

    For most people, the main internal antioxidant that protects against Alzheimer’s disease is glutathione. There is almost a direct correlation between declining levels of glutathione, rising levels of oxidative stress, and the onset and progression of Alzheimer’s disease.

    If a person has low levels of glutathione, they can have relatively low levels of oxidative stress and still develop Alzheimer’s disease. If a person has high levels of glutathione, they can have high levels of oxidative stress and not develop Alzheimer’s disease. A person with high levels of oxidative stress and low levels of glutathione are likely to die from another disease first. I presume most of the difference in glutathione levels between individuals is genetic as one cannot at this point get glutathione into cells (or at least not in significant amount).

    Oxidative stress does occur in other parts of the brain and affects others types of neurons and this may partially explain other neurodegenerative disease (and other diseases in other parts of the body). Oxidative stress, though, particularly affects the hippocampus because of myo-inositol levels there and the high expression of certain receptors that trigger Alzheimer’s disease (such as muscarinic acetylcholine receptors and NMDA receptors, for example).

    Nitrotyrosine levels are high in people with Alzheimer’s disease and this is critical because tyrosine nitration is an important factor in Alzheimer’s disease. Now, as you have pointed out before, peroxynitrite are not the only cause of tyrosine nitration but I can show how most of the risk factors for Alzheimer’s disease increase peroxynitrite, so if not the sole cause of this nitration it is a major cause.

    So far for every question, there is an answer. This is not a sign of cherry picking, it is a sign of a strong hypothesis. Once there is not an answer or when contradictory evidence is provided then I start working on an alternative hypothesis.

    1. Mark Thorson says:

      Baloney. Your hypothesis is trivially refutable and your argument rests on cherry picking and selection bias. As you already know, smokers are chronically exposed to high levels of peroxynitrite. If this were a risk factor for AD, we’d see a strong association between smoking and AD, and we’d see AD developing in young to middle-age smokers. We don’t see any of that. If anything, smoking is protective against AD.

      1. Lane Simonian says:

        Most young to middle age smokers die from lung cancer before they have a “chance” to develop Alzheimer’s disease, so the studies indicating that moderate to heavy smoking increases the risk for Alzheimer’s disease are probably underestimating the risk.

        1. Mark Thorson says:

          That would only be a problem in a prospective study. This was a meta-analysis of retrospective studies. Smoking is neutral or protective — exactly the opposite of what would be expected if peroxynitrite was a risk factor. In fact, if peroxynitrite was the central causal factor, it should have a very strong effect. It is evidence of your blinders that you dream up bogus excuses to ignore data that refutes your pet theory. Scientists don’t do that. Cranks do that.

          1. Lane Simonian says:

            One more time for you, Mark.

            Overall, literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD.


          2. Mark Thorson says:

            As has been pointed out to you before, that paper is a review combined with a report from a study using florabetapir to image amyloid deposition. It is not a meta-analysis, and therefore not a systematic analysis of the studies which have addressed the effect of smoking on AD. As the authors admit in the very first sentence:

            Cigarette smoking has been linked with both increased and decreased risk for Alzheimer’s disease (AD).

            Yeah, sure, if you want to include a few outlier studies with the bulk of the literature which shows no effect or a protective effect. There’s no accept/reject criteria for what studies they cite, because it’s not a meta-analysis. They just cherry pick studies which seem to support their speculations and ignore the rest.

            But in your crankitude, you just can’t accept any reliable evidence that overturns your cherished delusions. There is no evidence, no matter how compelling, that would dissuade you from your pet theory. You’ve got too much ego invested in it.

  20. SGM says:

    Amyloid beta may be an antimicrobial peptide, in which case the infection hypothesis and amyloid hypotheses would be compatible. And perhaps the infection that leads to the amyloid aggregation (which may be necessary but not sufficient for Alzheimer’s development) occurs decades before symptoms begin. So if healthy “older patients” are dosed with prophylactic antibiotic therapy — how young would they need to be in order to have some confidence that we’re not locking the barn door after the horse has already escaped?

    1. Lane Simonian says:

      Amyloid oligomers (or probably more accurately the copper and zinc which contribute to hydrogen peroxide formation) are antimicrobial. Amyloid plaques by entombing copper and zinc stop the production of hydrogen peroxide. This is likely what is happening in the brains of people with prion disease (high levels of hydrogen peroxide that don’t stop the infection but heavily damage the brain), but unfortunately the formation of amyloid plaques does not occur rapidly enough.

  21. Lane Simonian says:

    Here is it in a nutshell:

    Alzheimer’s Disease (AD) is one of the most important neurodegenerative disorders in the 21st century for the continually aging population. Despite an increasing number of patients, there are only few drugs to treat the disease. Numerous studies have shown several causes of the disorder, one of the most important being oxidative stress. Oxidative stress is connected with a disturbance between the levels of free radicals and antioxidants in organisms. Solutions to this problem are antioxidants, which counteract the negative impact of the reactive molecules. Unfortunately, the currently available drugs against AD do not exhibit activity toward these structures. Due to the fact that natural substances are extremely significant in new drug development, numerous studies are focused on substances which exhibit a few activities including antioxidants and other anti-AD behaviors. This review article presents the most important studies connected with the influence of free radicals on development of AD and antioxidants as potential drugs toward AD.

    How is it that every risk factor for Alzheimer’s disease increases oxidative stress, that every drug designed to eliminate amyloid and tau have failed, and certain antioxidants have succeeded in partially reversing Alzheimer’s disease in several small-scale clinical trials, and yet millions of dollars continue to be plowed into amyloid and tau antibodies, and almost nothing goes into developing natural products as antioxidants for the treatment of Alzheimer’s disease?

  22. chiz says:

    Assuming for the sake of argument that AD is caused by some sort of infectious agent – virus, fungus, microbe, virino/nanobe, martian glogblot or whatever, then why would Downs syndrome increase the risk and why would apolipoprotein alleles be relevant?

    1. Me says:

      Intelligent question!

      My 0.02 is that I have no problem with the infection idea. And not because I think it’s the main, causative factor, but because AD is so multifactorial that I reckon effective treatment would involve a lot of things. If going down the infections route can alleviate X% of patient symptom, it’s X% in the right direction.

      But since the debate is still running, here’s a question:-

      – Did the studies on amyloid as an antimicrobial agent use eukaryotic cells as control? Ie is it just cytotoxic?

      1. Lane Simonian says:

        AD is a multifactorial disease, but it all leads to the same endpoint. Certain treatments may help a certain subset people early on (specific antibiotics and metal chelators, perhaps). On the other hand certain antibiotics (minocycline, doxycycline, etc.) and certain metal chelators (polyphenols such as ferulic acid, eugenol, etc.) that act as antioxidants may be of some help to all people throughout the disease.

        Individuals with Down syndrome (because they have an extra copy of the chromosome with the sodium/myo-inositol co-transporter), who have high sodium intake, and who have high glucose levels (glucose 6- phosphate is converted into myo-inositol) are all at greater risk for Alzheimer’s disease because of high levels of myo-inositol in their brain.

        High levels of myo-inositol will lead to high levels of amyloid (first oligomers and then plaques) and tau tangles but not necessarily to Alzheimer’s disease. The latter requires an exhaustion (or near exhaustion) of antioxidants in the brain.

        1. Mark Thorson says:

          The amyloid precursor protein gene is on chromosome 21, the chromosome triplicated in Down’s. You don’t need some strained crank-science mechanism to explain the increased incidence of AD in Down’s.

          1. Lane Simonian says:

            The route to the formation of the amyloid precursor protein is via the myo-inositol/phosphatidylinositol 3,4 biphosphate/phosopholipase C/protein kinase C [secretion of the amyloid precursor protein]/NMDA receptor/peroxynitrite/caspase-3 pathway [beta secretase cut in amyloid precursor protein].

            Moreover, the anti-amyloidogenic activity of SNP [sodium nitroprusside–a nitric oxide donor] is sGC/cGMP/PKG-dependent as evidenced by its reversal by sGC/PKG inhibitions, whereas the amyloidogenic activity of SNP is peroxynitrite-related and can be reversed by peroxynitrite scavenger uric acid.

            A team at the Institute of Psychiatry at King’s College London found people with Down’s syndrome have higher levels of myo-inositol in their brains…The molecule is known to promote the formation of amyloid plaques – a hallmark of Alzheimer’s.

            Once they reach the age of 40, almost all people with Down’s syndrome show the brain characteristics of Alzheimer’s disease – though they do not all go on to develop dementia.

            Happy Crank Day!

      2. Lane Simonian says:

        It is not amyloid oligomers and amyloid plaques that are antimicrobial. It is the increased formation of hydrogen peroxide via copper and zinc (which incidentally also lead to the aggregation of oligomers) and peroxynitrite which through nitration converts oligomers into plaques that are antimicrobial. Unfortunately with certain chronic bacterial and viral infections, the oxidants that are supposed to attack the infection end up damaging the brain.

        1. AF says:

          The ubiquituous zinc+B vitamin cocktails as a cause for Alzheimer’s????
          That’s an intriguing thought

  23. Lane Simonian says:

    Zinc in relationship to the pathways that lead to Alzheimer’s disease is a problem.

  24. anon says:

    Gentleman! Please some decorum!

    Genes in the Down Syndrome Critical Region including DYRK1A and DSCR1 might provide some insight into the genetic question.
    Genes in the Down Syndrome critical region including DYRK1a and DSCR1 might provide some insight into the genetic question.

    1. Mark Thorson says:

      Sure, that might explain the mental retardation seen from an early age in Down’s, but the AD doesn’t develop until much later. The gene for amyloid precursor protein is on chromosome 21, so Occam’s razor suggests that any more convoluted hypothesis unsupported by compelling evidence is rightly consigned to the crank bin. It’s excess amyloid production, end of story.

  25. Kevin McLaughlin says:

    Anyone care to comment, Lane perhaps, on this study, which is available as a free pdf ?

    1. Lane Simonian says:

      Copper and zinc which play a role in the aggregation of amyloid into oligomers increase hydrogen peroxide early in Alzheimer’s disease and copper may play a role in the degradation of hydrogen peroxide into hydroxyl radicals early in Alzheimer’s disease, as well. I do believe, however, that amyloid plaques (which are the product of tyrosine nitration) are inert endpoints due to the absorption of copper and zinc.

      The “breakdown” of peroxynitrite via oxidation and the nitration can produce hydroxyl radicals as well and that is likely the primary if not sole source of hydroxyl radicals as the disease progresses.

      Perhaps the key point is this: it is not the amyloid oligomers and plaques that produce oxidants; oxidants produce amyloid oligomers and plaques (and also nitrate and prevent the dephosphorylation of tau tangles). A person can have plenty of amyloid (oligomers or plaques) and tau tangles in their brain and not have Alzheimer’s disease as long as the oxidants are being removed in sufficient amounts.

    2. Me says:

      I like the work. It’s all done in vitro though. No telling what’s going on in vivo. Any protein incubated in solutions of ions can sequester them and become redox-active. What does it mean in the grand scheme of things? There are plenty of other insoluble proteins in functioning cells that you could probably do the same experiments with.

  26. bank says:


    AD in Down’s is indeed mostly likely due to excess APP, however, it is not necessarily due to excess amyloid. Note that 1) the straight-forward hypothesis of excess amyloid causing AD has failed every straight-forward test, from mice to humans; 2) amyloid deposition in the brain does not correlate well with late-onset AD in the human population; 3) Abeta 42 in human CSF is now firmly established as *declining* with disease progression, CSF Abeta 40 does not change with disease progression … the list goes on….

    1. Me says:

      Agree on most/all of the facts you present. Most of them pretty easy to refute.

      Not sure what studies suggest clearing amyloid has not worked – since most of the ones I’m aware of are either indirect (small molecule stuff etc) or not penetrating CNS (MAbs).

      1) the straight-forward hypothesis of excess amyloid causing AD has failed every straight-forward test, from mice to humans. – Which studies? I haven’t seen one that provides a ‘silver bullet’. Although I certainly believe that what we see A->B-C->amyloid deposition->D->E etc. rather than amyloid deposition->A->B etc. IE I think amyloid deposition is a consequence of something else, and not that everything hinges on amyloid deposition.

      2) amyloid deposition in the brain does not correlate well with late-onset AD in the human population. True – symptoms lag amyloid deposition, but that doesn’t necessarily negate the hypothesis. Synaptic plasticity is aiding here. Same is seen in PD, where symptoms don’t kick in until pathology is well established

      3) Abeta 42 in human CSF is now firmly established as *declining* with disease progression, CSF Abeta 40 does not change with disease progression – easy to explain with a simple 2-compartment model using equilibrium dynamics etc.

      1. Mark Thorson says:

        In Amyloid Hypothesis 2.0, the problem in the common form of AD is not excess amyloid production — it’s impaired amyloid clearance. So the seemingly paradoxical decline in CSF amyloid is actually explained, it’s being kept in the CNS.

        A remarkable aspect of amyloid is its high turnover. A radiotracer study indicated pretty much all of the amyloid is replaced in about 2 weeks in a normal person.

        1. Me says:

          Thanks – any indication on the difference between AD and non-AD? I know a lot of guys that think autophagy is the way to go in AD research!

  27. bank says:


    Indeed there are numerous ways one could account for the paradoxical evidence regarding the amyloid hypothesis; oligomers rather than monomers, clearance rather than deposition, etc, etc.

    On the other hand, most AD-associated presenilin mutations are loss rather than gain of proteolytic function. The ones commonly used in mouse models have gain of protelysis, or shift the product ratio in favor of Ab42 — but they are selected for use precisely for that reason rather than being representative of all AD-causing presenilin mutations. Furthermore, some mutations in either APP or presenilin cause AD without being associated with increased amyloidosis (which is completely absent in APP Osaka, for example).

    Unfortunately I don’t think the debate is going to be resolved very soon unless someone can manage to generate a mouse that both accumulates amyloid plaques and gets tauopathy without having to introduce mutations into either APP or presenilin…

  28. Solo says:

    Thank you for sharing

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