Alzheimers

The amyloid-beta peptide forms insoluble clumps in the brains of patients with AD, and may be responsible for neuronal death (the amyloid hypothesis) . There have been many efforts to treat Alzheimers, most based on the dominant amyloid hypotheses. None have worked.

For quite a while, some have suspected that pathogens might be the primary cause of AD, but the idea has never been very popular with the funding agencies, or with most medical researchers. For example, there was some evidence that HSV-I increases Alzheimers risk, but there was a common objection: since healthy oldsters often have HSV-I in the brain, it can’t be the cause. In much the same way, many MDs said that h. pylori couldn’t be the cause of duodenal ulcers or stomach cancer, since it is found in large numbers of healthy people. It is the cause, though. Most people carrying the tuberculosis germ don’t get sick either – but nobody gets tuberculosis without it. In recent decades I think that few MDs say that therefore Mycobacterium tuberculosis is not really the cause of tuberculosis. Why don’t they? – the ‘logic’ is the same. I leave that as an exercise for my readers.

Some disease syndromes almost have to be caused by pathogens – for example, any with a fitness impact (prevalence x fitness reduction) > 2% or so, too big to be caused by mutational pressure. I don’t think that this is the case for AD: it hits so late in life that the fitness impact is minimal. However, that hardly means that it can’t be caused by a pathogen or pathogens – a big fraction of all disease syndromes are, including many that strike in old age. That possibility is always worth checking out, not least because infectious diseases are generally easier to prevent and/or treat.

There is new work that strongly suggests that pathogens are the root cause. It appears that the amyloid is an antimicrobial peptide. amyloid-beta binds to invading microbes and then surrounds and entraps them. ‘When researchers injected Salmonella into mice’s hippocampi, a brain area damaged in Alzheimer’s, A-beta quickly sprang into action. It swarmed the bugs and formed aggregates called fibrils and plaques. “Overnight you see the plaques throughout the hippocampus where the bugs were, and then in each single plaque is a single bacterium,” Tanzi says. ‘

If this new picture turns to to be correct, some combination of fighting & preventing the relevant pathogens, perhaps combined with methods of removing excessive amyloid buildup, would probably be fruitful.

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54 Responses to Alzheimers

  1. You leave us with the exercise of working out why this argument was in error: “there was some evidence that HSV-I increases Alzheimers risk, but there was a common objection: since healthy oldsters often have HSV-I in the brain, it can’t be the cause.” Was it due to a failure to understand that a particular cause can be necessary, but not sufficient?

    • AnonymousCoward says:

      That’s not quite what he says. Rather, he leaves us to work out why the same (erroneous) argument has not been used to counter-argue the Mycobacterium Tuberculosis bacterium being causative of tuberculosis.

      • AnonymousCoward says:

        My guess as to the answer to the question is similar to the answer to the question of why Cochran’s “contagious homosexuality” hypothesis is not commonly pursued.

        Stigmatization.

        People are (far) more frightened of Alzheimers infection than of tuberculosis infection, or stomach ulcer infection.

        Exploration of hypotheses tuberculosis and stomach ulcers being caused by infectious vectors is tolerable, because we’re not deathly afraid of those diseases. While exploration of hypotheses of Alzheimers being contagious via a vector will lead to stigmatization of sufferers, and risk accusations of the hypothesizer being causative of said stigmatization.

        • Frau Katze says:

          It seems there’s quite a few diseases where you can test positive but not have any symptoms. Another one is typhoid. People should start at least worrying a bit about TB, as drug resistant cases are out there, just give it time.

    • Dale says:

      Two good indicators of a pathogen origin is if all patients show infection by a particular agent and if there is a substantially different MHC profile between the patients and the non-patients. E.g., in tuberculosis, all people who present with the disease are identifiably infected.

  2. Sandgroper says:

    Whatever, I wish they’d bl**dy hurry up, because I’m definitely turning strange.

  3. Clathrus says:

    Too late for Terry Pratchett, unfortunately.

  4. Patrick Boyle says:

    There are some fascinating consequences of ignorance of the infectivity of tuberculosis. One of these is the effect on Italian opera.

    Infection as a cause of many diseases only came into medical consciousness in the last years of the nineteenth century with Koch and Pasteur. But two of the greatest and most popular operas were written before germ theory was universal recognized. Those are of course – Traviata by Verdi early in the century and La Boheme by Puccini late. In both of these masterworks when conventionally stage the tenor frequently gives the tubercular soprano a number of big passionate kisses. This is not a good idea. I worked in a tubercular ward when I was in the Army. It was only one day at SF General. But I knew about germs and it was for me, a very creepy and uncomfortable day. I couldn’t possibly have kissed a tubercular woman.

    This is another reason why updating operas or plays to modern times seldom works.

    When Traviata was written a lot of the public still thought that consumption (tuberculosis) was caused by vampires.

    • Dale says:

      I’ve seen writers say that in La Boheme, tuberculosis is a stage-code for syphilis, with the background of the plot that being in the Bohemian subculture and practicing free love in the late 1800s put one at definite risk of a slow death by syphilis.

      • Tuberculosis was so common that it wouldn’t have served as a good stage code for anything. (Murger, who wrote the original Boheme book, himself died of TB.) Besides, the course and symptoms of the two diseases are very different.

  5. M says:

    As a carrier of HSV-1 from very early in life, now being 44 y/o, its link as a possible trigger of Alzheimer’s is really scary to me. 😦

    Anyway, just wanted to mention something tangential:

    I have had outbreaks of cold sores regularly for most of my life, on average probably about every 3 or 4 months, but I’ve been free from them for about 3 years now, ever since I started taking two megadoses of Valaciclovir with a 12 hour period between them (as per instructions) when I notice the typical itching and tingling sensation right before an outbreak.

    Just wanted to mention it, in case anyone else here have problems with regular cold sore outbreaks. Aciclovir did nothing for me, but Valaciclovir has been working perfect.

    By the way, given the link of HSV-1 to AD, I’m thinking about starting to take Valaciclovir as a regular daily dose (as people with HSV-2 are recommended to do) on the possibility that it will make my immune system release less Amyloid-β as a defence against the virus.

    Any immunologists here who could weigh in about what they would do in my situation?

    • HSV-1 is not the only germ that’s been implicated; check out the work of Brian Balin for research implicating chlamydia pneumoniae. One of his papers studied brains from people who had died from Alzheimers, reporting that “we routinely found about 20% of neurons to be infected with the organism.”

      (Chlamydia pneumoniae isn’t the sexually transmitted disease; that’s a different germ, chlamydia trachomatis.)

    • ohwilleke says:

      I hate to be pessimistic but AD appears to have a very slow progression, so an infectious cause far removed from symptoms is plausible. Retrospective studies of nuns diagnosed with AD post-mortem detect subclinical symptoms in their written work starting in their 20s or 30s around the time that they take Holy Orders, suggesting a gradual progression over more than 30 years in the typical case.

  6. pyrrhus says:

    I have seen research suggesting that the amyloid plaques aren’t the problem in AD, that it is damaged microtubules….but the damage may well be caused by a pathogen. There is speculation that whatever protects the microtubules from damage may be impaired by heavy metals, or unknown toxins.

    • reiner Tor says:

      There is speculation that whatever protects the microtubules from damage may be impaired by heavy metals

      I hope thrash and death metals are not nearly as harmful!

  7. MawBTS says:

    One of the lines of evidence for a gay germ is that there are populations that don’t have homosexuality.

    I wonder…how is Alzheimers distributed globally? Are there primitive tribes that don’t get it?

    • granesperanzablaco says:

      Related to this, heterozygous carriers of the APOE4 variant of apolipoprotein E have higher rates of AD and homozygotes E4/E4 still higher rates

      I have read that this is less true in traditional cultures eating traditional diets (don’t know if this is conclusive) and that APOe4 is ancestral

      Would be interested in any insight here

  8. j says:

    If Alzheimer was caused by bacterial pathogens like Salmonella, it should be prevented by antibiotics. Apparently it is not. But some Salmonella lines like those causing meningitis in babies laugh off all known antibiotics.

    • Cloudswrest says:

      “Moreover, antifungal treatment in two patients diagnosed with AD reversed clinical symptoms51,52. The interpretation of these results was that perhaps these patients were misdiagnosed. ”

      From here: http://www.nature.com/articles/srep15015

    • pauljaminet says:

      Most antibiotics do not kill, they just induce dormancy. This gives immunity a leg up, but that only makes a big difference in acute infections in which the pathogen reproduces frequently and is killed frequently. In pathogens that reproduce slowly and are good at hiding from the immune system, you would have to take the antibiotics for years or decades to see an effect. That is not feasible due to negative side effects. Another issue is that some antibiotics do not enter the brain well.

      • j says:

        I know, Paul. The discouraging conclusion is that even if Alzie was caused by pathogens, as of today we could do little to prevent/cure it.

    • Andrew Ryan says:

      Many commonly used antibiotics do not cross the blood brain barrier and are not take at sufficient doses or lengths of time to eradicate microorganisms from the brain.

  9. The Man Who Was . . . says:

    Most people with either form of HSV don’t have symptoms.

  10. pauljaminet says:

    It’s been evident for a long time that Alzheimer’s was infectious in origin, I blogged about it in 2010: http://perfecthealthdiet.com/2010/06/is-alzheimer%E2%80%99s-caused-by-a-bacterial-infection-of-the-brain/.

    The primary reason researchers and funding agencies don’t want to believe in infectious etiologies is that only about 1% of academic researchers have the skills or facilities to study biohazards like infectious pathogens, whereas all can do molecular and cellular biology on mice and humans. It’s not easy to persuade a study section that 99% of funding should go to 1% of researchers.

    Just like it’s not easy to persuade the drunk to look for his keys in the darkness, if he’s being paid to look under the streetlamp.

    • Rick says:

      I don’t think this is fair. It is very clear that Alzheimer’s has a strong genetic component. But… the genes involved don’t give a clear-cut answer as to the cause.

      On the other hand… the infectious agents involved seem to be extremely undefined (bacterial, fungal, viral), which leaves open the strong possibility that it is a secondary problem.

      I think the case is now much stronger that it is a combinational problem of an overactive innate immune response to ‘normal’-ish pathogen(s) of the brain.

      So the real questions are… Why is it increasing in frequency? (Is something else making the response excessive, or are the agents increasing, or is it just that people are living longer?) What can be done? (Get rid of the infections (which seems like a losing battle), or prevent the response to those infections.)

      • j says:

        We could move to sterile space colonies.

      • gcochran9 says:

        It’s decreasing in frequency, age-adjusted. Probably.

      • pauljaminet says:

        What is a “normal-ish pathogen of the brain”?

        If normal means common, well yes, all the likely infectious Alzheimer’s causes are very common in the elderly. Most people have at least a 1% chance per year of picking up each infection,

        If normal means benign, none of these are benign, even if they have no effect but to parasitize resources. As the infectious burden per cell grows, they begin to starve brain cells. The metabolic system of the brain is designed only to provide a fixed amount of resources. When these are shared between neurons and pathogens, the neurons suffer.

        The immune response to these pathogens is also harmful. For example, interferon gamma mediated immunity reduces production of serotonin and melatonin, with significant effects on mood and health.

        Whether the harm is due to the immune response, parasitic burden, or other harmful effects of the germs, it is likely that the cumulative effect of multiple pathogens causes the loss of cells, the aggregations, and the cognitive deficits.;

        “The infectious agent is undefined” — because it is not a single infectious agent.that is causing the problem. Every microbe capable of establishing chronic infections contributes to the problem, because every one of them consumes scarce resources and evokes immune responses with bystander effects.

        Nor is “overactive” a good description of damage from immunity. “Ineffective” immunity would be a better description. If the immunity succeeded in clearing the infections, the immune response would go away even if it had been “overactive” at one time.

        • Rick says:

          I mostly agree here.

          By normal-ish, I only meant that these are very common and not unusual in any specific way, as in the causes of most infectious diseases.

          As for the immune response simply being simply inefficient, as opposed to abnormal or overactive, I think you could be wrong. If this response simply eliminates the microbes in younger people, then why not in older people as well?

          Old people clearly coat the invading bacteria/fungi/viruses in large amounts of the amyloid protein, and presumably this ‘kills’ them, yet the response keeps going after them anyway, with ever increasing amounts of buildup. Perhaps clearing out the buildup is the problem?

          Even though we know a hell of a lot, it certainly is not cut and dry. We still have few leads on treatment or prevention. I would suggest that prevention by focusing on the microbes is insane. We have to focus on the innate response in this case.

          • pauljaminet says:

            The immune response doesn’t eliminate the microbes in young people. Rather, the infectious burden, i.e. the number of cells infected and the number of microbes per cell, increases continuously and in the elderly the effects become apparent.

    • gcochran9 says:

      Fashion in the funding agencies may matter more.

    • Economic Sophisms says:

      Paul, haven’t there been anecdotal cases in the paleosphere of people effectively treating AD with ketogenic diets and coconut/MTC oil? What do you make of that? Hype to sell books?

      • pauljaminet says:

        Yes. Mary Newton’s husband, who died earlier this year, was the poster boy for it. See http://www.coconutketones.com/.

        It is real, in that generally bacteria cannot utilize ketones, and ketogenic dieting can greatly reduce glucose and pyruvate concentrations in the brain, so ketogenic dieting will help the brain fight bacterial infections. Of course this won’t help much against viral (HSV-1), protozoal (toxoplasma), or fungal infections. It should slow progression of the disease in most cases. It is not a cure.

  11. Jim says:

    Greg – My doctor remarked to me once that he suspected that the high rates of obesity in the US today might be due to some kind of virus or other pathogen. What do you think of this theory?

    • gcochran9 says:

      It’s possible – there are viruses that show this effect in experimental animals.

      • Rick says:

        Not likely.

        In my opinion, most of the evidence points to excess artificial light disrupting circadian rhythms, while excess sugar is always at the ready for the increase in abnormal feeding times associated with those disruptions.

        The increase in obesity is perfectly linked to the availability of cheap electricity. While this is a very complex association, it seems to follow the physical power grid more than the availability of high-sugar foods, which can easily travel to out of the way locations.

        • gcochran9 says:

          “perfectly linked to the availability of cheap electricity.”

          since the 1980s? No.

          • Rick says:

            Not just electricity, the devices that run on that electricity. Not many young kids stayed up til midnight playing video games and watching television before the 1980s. Now an ever increasing number of kids and adults also have a bright phone or tablet that they keep by their bedside.

    • dearieme says:

      As evidence for the theory I like to cite the disproportionate numbers of waddlers who are employed in British hospitals. They must be exposed to far more pathogens than most people. I’d like to see ‘before-and-after’ photos of the staff.

    • Greying Wanderer says:

      sugar

  12. Old fogey says:

    We frequently hear about research to fight specific diseases, but I don’t think I’ve ever heard of a major effort devoted to a study of the immune system as a whole. Have the charities devoted to fighting cancer and heart disease, for example, ever spent money in this way?

  13. JP Straley says:

    “…some way to remove excessive beta amyloid buildup…” posits Mr. Cochran.. To which I reply, use “Neurophage” in your browser and you will find a very interesting answer to the question he poses.

    JP Straley

  14. erica says:

    http://www.iflscience.com/brain/vessels-found-connect-immune-system-and-brain

    ” ‘It changes entirely the way we perceive the neuro-immune interaction,’ says Kipnis. ‘We always perceived it before as something esoteric that can’t be studied. But now we can ask mechanistic questions.'”

    Won’t it take something like this, an actual anatomical/physiological discovery to convince those who have the research dollars to investigate bugs and brains? While the medical field has been accustomed and comfortable treating pathogen attacks on our respiratory system, they seem not to have given the same attention to bugs and other systems: the circulatory, neurological, endocrine, reproductive systems are just as likely to be targets/victims of pathogen attacks, aren’t they? Isn’t that logical?

    For instance, while they understand that reproductive organs are attacked by germs, leading to infection and possible dysfunction, they seem not to consider the possibility that the organ that controls that system might fall victim to bugs as well. It seems to me that medical science has been content to conclude that few pathogens can actually get across the BBB and so seem to have shrugged as if to say, “Well, yeah, sure, there’s encephalitis and meningitis, but it’s unusual for much of anything else to cross the BBB.”

    The BBB is obviously not a perfect system protector, and you’d have thought that money to study the brain, the control center for the entire system, would have evoked more interest and more dollars. Perhaps there is fear in finding answers to questions about many human behaviors.

  15. spottedtoad says:

    If it is infectious, nursing homes are a very bad idea indeed.

  16. Andrew Ryan says:

    Very interesting study. If I had to bet $$$ I would go with prions as an AD culprit–they have both infectious and heritable properties and extraordinarily difficult to identify in tissues as they lack nucleic acid.

  17. sprfls says:

    What about depression?

    I realized in myself (n=1) that I began feeling depressed exactly at the same time when I began having insane allergies, neither of which I ever had previously, at all. Autoimmune diseases run in my family (Crohn’s, psoriasis, arthritis, etc.)

    Also, the stark dichotomy between African and non-African depression rates is also telling, given the recent Neanderthal paper which found that Neanderthal alleles are associated with “neurological, psychiatric, immunological, and dermatological phenotypes.”

    My spidey sense tells me it’s all somehow related, even if I’m not sure exactly how.

    • Rick says:

      At the risk of sounding like a broken record, or just crazy, I would focus your attention on Circadian Clock genes and how they interact with the environment.

      Just looking at suicidal behavior, circadian clock genes are overrepresented among the top markers. Notably, PER1 and CSNK1A1 variants strongly predict hospitalization rates. Circadian clock abnormalities are related to several mood disorders besides just depression, as well as being implicated in immune disfunction, obesity, diabetes, and, of course, sleep abnormalities.

      The ancestors of modern humans have been genetically entrained to light cycles and frequencies for literally billions of years. Now whole societies spend most of their time indoors and see no possible problem arising from switching from incandescent to fluorescent to halogen to LED bulbs as prices of electricity and bulb technologies change. Or to just shine bright lights in their eyes at any random hour of the day or night.

      The single most effective treatment for depression is light therapy. If you do literature research for 10 minutes you will know tht this is 100% true.

  18. Peter Borregard says:

    Dale Bredesen and his colleagues have identified three metabolic subtypes of Alzheimer’s disease: inflammatory (which is where the infectious agents particularly come in, though the underlying inflammatory burden based on other factors, particularly blood glucose and insulin, are major players as well;) non-inflammatory, where the major drivers are insulin resistance, low vitamin D, elevated homocysteine and sex hormone insufficiency (early oophorectomy is a predisposing factor, for example;) and cortical (patients tend to be ApoE4 negative;) which Bredesen contends is qualitatively different from the other two; it is often associated with low serum zinc (a pretty insensitive test, though not prone to false positives: if your serum zinc is low, you’re deficient, but if it’s “normal” it doesn’t exclude deficiency.)

    http://www.impactaging.com/papers/v7/n8/full/100801.html

    He writes, “…the past few decades of genetic and biochemical research have revealed an extensive network of molecular interactions involved in AD pathogenesis, suggesting that a network-based therapeutics approach, rather than a single target-based approach, may be feasible and potentially more effective for the treatment of cognitive decline due to Alzheimer’s disease” and has proposed a promising approach for arresting and even reversing cognitive decline.

    http://www.impactaging.com/papers/v6/n9/full/100690.html

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