7 ms·

>"we’re beginning to think previously unthinkable thoughts" What made it so previously unthinkable? AFAIK, there was a rough correlation between presence of th

• jcranmer 8y ago
  Well, the hypothesis was tested on data... that data being drugs to reduce amyloid plaques, which have only recently been found to not work to ameliorate Alzheimer's. The amyloid hypothesis looks to be an open-and-shut case of "correlation does not imply causation." The problem is, we don't know what actually causes Alzheimer's, and for the longest time, the amyloid plaque correlation was the only thing that looked like it could be a cause. On top of that, actually testing these hypotheses takes a long time, especially if you take the not-unreasonable attitude that tackling them after on its onset (i.e., before it's readily detectable) may be too late.
  • nonbel 8y ago
    >"Well, the hypothesis was tested on data... that data being drugs to reduce amyloid plaques, which have only recently been found to not work to ameliorate Alzheimer's." Right now I'm not even interested in how accurate the amyloid hypothesis turns out to be[1], but as you say its only recently the the hypothesis been tested. Sure, maybe it is just hard to test it, etc. But, why did people find it "unthinkable" to consider the hypothesis was incorrect before it was ever really tested? I feel like there is a really good example of philosophy/sociology of science fail to learn from here. The problem I'm interested in isnt with the hypothesis itself, its with the seemingly unwarranted very strong belief in the hypothesis amongst the "experts". [1] When I first learned amyloids are one of the most thermodynamically favorable states of polypeptides and the cell must devote constant resources to preventing their formation, I pretty much gave 99/1 odds amyloids are a symptom instead of cause.
    • tim333 8y ago
      Being a little cynical the reason for the "unthinkable" thing may be in the article: > “The government and the pharmaceutical industry have invested almost all their resources, and some of the brightest people have been in the amyloid area,” he says Not so much unthinkable but if you speak that thought those invested may attack you in the political "grant applications have negative feedback" sense. You see that quite a lot that when people have built careers based on hypothesis A they do not take kindly to the idea of A being wrong.
  • jamesblonde 8y ago
    This is far from the whole story. The pathology of alzheimers as predicted by the Amyloid Hypothesis is (year 0) imbalance in the production, (year 10-30) deposition of abeta causes Tau and other downstream complications that are symptomatic. Existing clinical studies started way too late, after the appearance of significant sympthoms - at least mild cognitive impairment. Personally, i take curcumin supplements, as it is known to bind to abeta even in the cerebrospinal fluid, then it gets cleared out over the blood brain barrier. If the abeta hypothesis is true, high dose curcumin should help delay its onset. Another thing to do is get your genome sequenced, even with 23andme. If you have apoe4, you should, IMO, take curcumin.
    • exhilaration 8y ago
      Would you mind sharing which curcumin supplements you take? I'm currently taking one 750mg capsule of curcumin per day but I've been considering switching to theracurmin after reading about it in Hacker News comments.
      • jamesblonde 8y ago
        I take biocurcumax. Curcumin with bioperine is also good - i wouldn't take theracurmin, though. Afaik, it has lots of downstream curcumin metabolites, and they aren't anti-inflammatory/abeta-binding.
    • nonbel 8y ago
      Fyi, I have no idea if your regimen (or any) of curcumin is good for you or not but amyloid beta may be protective in some way: >"Mice with excess beta-amyloid survived longer than the controls and had less bacteria in their brains. Mice lacking beta-amyloid (from the genetic removal of APP) died more often from infection." https://www.nih.gov/news-events/nih-research-matters/alzheimers-protein-may-have-natural-antibiotic-role https://www.nih.gov/news-events/nih-research-matters/alzheim...
      • jamesblonde 8y ago
        Curcumin won't clear out all abeta. Just bind to some and clear it. It also dampens anti-inflammatory pathways (e.g., mild inhibitor of TNF-alpha production). I see the cost-benefit being overall positive for medium-dose curcumin (like 500mg-1g/day).
• JamesBarney 8y ago
  I think the correlation was a bit different. It's my understanding not everyone with amyloid build up had symptoms, but everyone with a confirmed AD diagnosis had amyloid build up.
  • nonbel 8y ago
    I quickly found this, it looks like its based off a conference presentation but know there are older sources saying about the same: > "So far, the results have been dramatic. Among 4,000 people tested so far in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, researchers from the Memory and Aging Center at the University of California at San Francisco found that just 54.3 percent of MCI patients and 70.5 percent of dementia patients had the plaques. A positive test for amyloid does not mean someone has Alzheimer’s, though its presence precedes the disease and increases the risk of progression. But a negative test definitively means a person does not have it." https://www.washingtonpost.com/national/health-science/brain-scans-show-many-alzheimers-patients-may-not-actually-have-the-disease/2017/07/18/52013620-6bf2-11e7-9c15-177740635e83_story.html https://www.washingtonpost.com/national/health-science/brain... What they do is use a circular definition of: Alzheimers symptoms + amyloid-beta = alzheimers disease Alzheimers symptoms - amyloid-beta = other disease So I don't disagree that technically "everyone with a confirmed AD diagnosis had amyloid build up", just that this is true by definition.
    • jcranmer 8y ago
      Dementia is essentially a phenotype rather than a specific pathophysiology. (I know someone who died of a non-Alzheimer's form of dementia, specifically vascular dementia). I don't know what the exact definition of Alzheimer's is, but I believe it's based primarily on the neurodegeneration of the cerebral cortex rather than the definitive presence of amyloid buildup.
      • nonbel 8y ago
        Whatever the details, they were diagnosing people and giving them "Alzheimers drugs" until they saw lack of amyloid-beta. To me it sounds like the "definitive evidence" is "telltale amyloid deposits": “If someone had a putative diagnosis of Alzheimer’s disease, they might be on an Alzheimer’s drug like Aricept or Namenda,” said James Hendrix, the Alzheimer Association’s director of global science initiatives who co-presented the findings. “What if they had a PET scan and it showed that they didn’t have amyloid in their brain? Their physician would take them off that drug and look for something else.” For decades, diagnosing Alzheimer’s has been a guessing game, based on looking at a person’s symptoms rather than testing for definitive evidence of the brain disorder. A firm diagnosis was not possible until an autopsy was performed. Now, a spinal tap or PET scan can detect the telltale amyloid deposits, and researchers are trying to develop a simple blood test that would do so. PET imaging can quantify the amount of amyloid and also show where it is in a person’s brain."
• taeric 8y ago
  More that it was unfunded. A large part of that is likely that it is difficult to fund a method nobody else is investigating. Specifically, to heavily fund it.
  • nonbel 8y ago
    What was unfunded, the amyloid hypothesis? If the hypothesis was not fully investigated, it may be ok to tentatively accept it anyway. But I don't see how dropping it later became an "unthinkable thought". Also, if you are talking about the amyloid hypothesis, I think you could hardly call it "unfunded", it is probably one of the most well-funded medical hypotheses.
    • taeric 8y ago
      Apologies, I meant I was guessing the original poster used "unthinkable" where they meant "unfundable." And even there, I was expecting it to mean "largely unfundable." With little in the way of results elsewhere, it is hard to justify large spending elsewhere.
      • nonbel 8y ago
        Ok, I get what you are saying now, but not how you could interpret this statement that way: > 'we’re beginning to think previously unthinkable thoughts like “what if the hypothesis the last 20 years of research was based on (beta amyloid plaques)is just totally wrong”.'
        • taeric 8y ago
          I took the parent's claim to be more that most of the alternative research just didn't seem to be happening. It wasn't that people didn't think it Alzheimer's couldn't be virus/whatever related; but it was widely true that no funded research was looking into that. Instead, a large portion of the funding went into the "amyloid hypothesis." That make sense? I mean, yes, people could have thought this before. But, by and large, they didn't spend time throwing money down those thoughts.
• st26 8y ago
  What made it so previously unthinkable? Admitting you have invested twenty years of research and you're not an inch closer- in fact you went down the wrong path entirely- would be a pretty bitter pill to swallow, both for researchers and patients.
  • nonbel 8y ago
    So some sort of critical mass was hit after x years and if that bet was wrong they are doomed for the next 20-40? Why didn't they wait until an actual definitive prediction came true?
    • db48x 8y ago
      Nobody understand the brain well enough to do that yet. Furthermore, the existence of a cure for a disease goes a long way towards proving what the mechanism of the disease is.
      • nonbel 8y ago
        >"Nobody understand the brain well enough to do that yet." I'm fairly certain I understand the brain well enough to know our understanding of the brain is rudimentary and there is no reason to become attached to a vague preliminary model like this "amyloid hypothesis".
        • db48x 8y ago
          It's not so vague as it might sound. There's good evidence that people with amyloid plaque build-up, in the brain or in other organs, have different versions of the genes that code for the production of amyloid proteins than people who do not.
• db48x 8y ago
  The word "unthinkable" here is probably just hyperbole. There were other hypotheses, complete with papers published about them, but there was a lot less to support them than the amyloid hypothesis. Amyloid is simply the only obvious difference between someone suffering from Alzeheimer's and anyone else. As a result, at least half a dozen different pharmaceutical companies each spent billions to develop a therapy based on it. Since it generally takes around 10 years to develop a drug, they made those choices before a lot of the alternatives had any data to back them up. I'm no expert, but I'd be willing to bet that the recent study of the viral hypothesis couldn't even have been done 10 years ago. The fun thing is that even if you consider the amyloid hypothesis to be false, that doesn't make any of the alternative theories any more likely to be true; in 10 years we could be seeing another big round of failures. In fact, the amyloid hypothesis could still be true, but nobody has found the right way to tackle the problem.
  • nonbel 8y ago
    >"Since it generally takes around 10 years to develop a drug, they made those choices before a lot of the alternatives had any data to back them up." Its possible to act on a "working hypothesis" without it becoming anything close to "unthinkable" to consider other hypotheses. For some reason this amyloid hypothesis became well accepted and ingrained without good reason. >"The fun thing is that even if you consider the amyloid hypothesis to be false, that doesn't make any of the alternative theories any more likely to be true" This violates Bayes' theorem. >"In fact, the amyloid hypothesis could still be true, but nobody has found the right way to tackle the problem." Why don't the supporters of the amyloid hypothesis make a definitive prediction, then if it doesnt work out the hypothesis can be dropped?
    • db48x 8y ago
      > Its possible to act on a "working hypothesis" without it becoming anything close to "unthinkable" to consider other hypotheses. For some reason this amyloid hypothesis became well accepted and ingrained without good reason. This is my point. It was never literally true that alternatives were "unthinkable"; the word "unthinkable" was a small bit of hyperbole on the part of the author of the quote we have been discussing. Just don't lose sight of the fact that the amyloid hypothesis did and still does have good evidence for it. (In addition to a whole load of new and very expensive evidence against it.)