11 ms·

A prospective Alzheimer’s trial reports

123 points by hprotagonist 7y ago

Numberwang 7y ago
I have hopes in the ongoing trials by Dean Ornish regarding Alzheimer's. It seems all other common age related health issues are improved by a vegan diet, so it will be interesting to see the results of this study.
wiremine 7y ago
Anyone have any breakdown of what this means for the laymen out here on HN? I get the gist this was a major (but not unpredicted) failure, but am I reading it wrong? Was this for one category of drugs, or a hypothesis about the cause of Alzheimer's in general, or both?
- exhilaration 7y ago
  There was a good HN discussion a few weeks back about this: https://news.ycombinator.com/item?id=21911225 https://news.ycombinator.com/item?id=21911225 It's becoming increasingly clear that the entire Amyloid-beta plaque hypothesis has been wrong and last 20+ years of Alzheimer's research and drug development has been wasted.
  - eganist 7y ago
    Yup, and the infectious theory is the one that's gradually getting more and more mainstream traction (the premise being that beta amyloid has a tactical immune function in the brain but trades short-term success against pathogens at the expense of long term longevity in people who can't clear the plaques out effectively with restful sleep). Good Google scholar queries include 'hsv apoe4' as well as 'gingivitis alzheimers', without quotes, and among others. I can dig up my past comments that went into depth on all the different studies here, but a lot of doctors have yet to be swayed on the new theory. Edit: found a good reference page with all the different trials going on around different theories for Alzheimer's, including the infectious theory. http://www.cumc.columbia.edu/adrc/patients-and-families/clinical-trials http://www.cumc.columbia.edu/adrc/patients-and-families/clin... has all the current trials https://clinicaltrials.gov/ct2/show/NCT03282916 https://clinicaltrials.gov/ct2/show/NCT03282916 is the valacyclovir trial trying to replicate the 2018 results out of Taiwan. A different angle is the recently discussed correlation between lithium intake and Alzheimer's, and that's also being explored: https://clinicaltrials.gov/ct2/show/NCT02129348 https://clinicaltrials.gov/ct2/show/NCT02129348
    - atombender 7y ago
      That clinical trials list doesn't mention the GAIN phase 2/3 trial [1] [2] currently underway to test COR388 from Cortexyme [3]. It's a small molecule that targets gingipains, cysteine proteases of the P. gingivalis, a periodontal pathogen responsible for gingivitis that has been found in Alzheimer's patients. Here [4] is a paper on the gingivalis hypothesis funded by Cortexyme. [1] https://clinicaltrials.gov/ct2/show/NCT03823404?term=NCT03823404&draw=2&rank=1 https://clinicaltrials.gov/ct2/show/NCT03823404?term=NCT0382... [2] https://gaintrial.com/en/about https://gaintrial.com/en/about [3] https://www.cortexyme.com/?page_id=6022 https://www.cortexyme.com/?page_id=6022 [4] https://advances.sciencemag.org/content/5/1/eaau3333 https://advances.sciencemag.org/content/5/1/eaau3333
    - nextos 7y ago
      It's not necessarily pathogens only but it can also be commensal dysbiosis. See the discussion linked by the parent comment or my other comment here. We should start thinking about all diseases that involve the HLA gene and dysfunctional immune responses as autoimmunity. Not just the obvious ones. Hence the question is simply why is the immune system misclassifying our own tissues? It's a CS / information theory problem.
  - nextos 7y ago
    Yes. My comment triggered most of that discussion. I have really good solid evidence for another common disease being caused by infection or microbiome dysbiosis. But I am encountering a lot of resistance in the field despite my theory, models and data being much more solid than the status quo to explain said disease and my research coming from a famous lab. I guess it's really hard for lots of people to accept most of their careers were spent chasing the wrong hypothesis. I've reached a tipping point where I think I can only push it further and develop a drug in a startup. Alzheimer's and Parkinson's are also something I want to tackle because the mechanism is analogous. If someone wants to help or some VC is interested, just let me know. Contact email is in my profile. These diseases have a big CS / information theory component.
    - Vomzor 7y ago
      What’s the disease? My personal experience and the research I’ve read makes me believe you are absolutely right.
      - deleted 7y ago
        [deleted]
      - esdott 7y ago
        Probably something like MS or another auto-immune disorder that could be microbiome and/or dopamine related. Could also be type 1 diabetes, RA, Crohn's, etc. Those would be my guess.
      - fernly 7y ago
        No idea if this is nextos's thing, but there's evidence for inflammation as a root cause of depression. cf Bullmore, the Inflamed Mind.
    - vikramkr 7y ago
      What's the disease and what's the resistance from the field? Microbiome stuff isn't as hot an area of investment as it was a few years back, but there's tons of biotech funding to go around (assuming you're in the US) and if you have solid data and an actionable drug, it shouln't be extraordinarily difficult to form a company around it in this economy.
  - jdhn 7y ago
    If the past 20 years of research & drug development have been wasted, how does the average person help steer the ship away from clearing the plaque, and more towards identifying and treating the cause of the plaque in the first place?
- deleted 7y ago
  [deleted]
- abhisuri97 7y ago
  Kinda both. Increased presence of amyloid (a type of protein) plaques are common in patients with Alzheimer's disease, so it was hypothesized that these plaques contribute to alzheimers. The drugs mentioned specifically targeted these plaques (via monoclonal antibodies). These drugs didn't slow the progression of alzheimers in the patient population that was certain to get it. The drugs could have failed for two reasons I think: 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue) or 2) the amyloid plaques themselves are actually being broken up by the drug...but the plaques may not really be a cause of alzheimers (in which case the hypothesis is the issue).
  - jcranmer 7y ago
    > 2) the amyloid plaques themselves are actually being broken up by the drug This is actually what several studies have shown--the amyloid plaques were being removed by the drugs, but the progression of Alzheimer's was not slowed or halted.
    - hprotagonist 7y ago
      Different disease, but if you really want to be depressed: https://blogs.sciencemag.org/pipeline/archives/2017/05/18/now-this-is-a-drug-that-does-not-work https://blogs.sciencemag.org/pipeline/archives/2017/05/18/no...
  - n0rbwah 7y ago
    > 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue) Shouldn't it be possible to have a look at the patients brains to see if there's any difference in plaque formation in those that underwent treatment vs those who had the placebo.
downerending 7y ago
tldr: No effect for the two antibodies tested.
streptomycin 7y ago
As that last-linked blog post makes clear, I don’t find that evidence compelling, and most certainly not compelling enough to approve the drug as it stands. But with the way the FDA is behaving these days, God only knows what’s going to happen. People are investing on just that basis, although rarely stated in quite those words. But if you can look at the ruins of all the attempts to show efficacy with anti-amyloid antibody therapies and decide that the Biogen/Eisai data represent a real ray of hope, you have a sunnier disposition than I do. I share the cynicism! Early drugs targeted amyloid plaques because it seemed like a good idea. But after so many failures, I can't think of any reason so much time and money is spent on a failed hypothesis other than hoping for a false positive. Because a false positive, even with very modest results, would result in a ridiculously profitable drug given the complete lack of Alzheimer's treatments we currently have.
- melling 7y ago
  Because there’s very little money is invested in Alzheimer’s research. People were very conservative in their choices. We were spending a lot more on AIDS research 20 years ago than on Alzheimer’s today: https://www.ncbi.nlm.nih.gov/books/NBK222902/ https://www.ncbi.nlm.nih.gov/books/NBK222902/ This produced great results for AIDS, which many people thought would never be treatable. Anyway, medical research is expensive. Considering the number of people who will get Alzheimer’s and the cost to deal with the disease, you would have thought we’d have been spending more on research for the past several decades. Maybe soon we will all agree that it’s probably worth investing more on research?
  - SAI_Peregrinus 7y ago
    FYI, AIDS is an acronym (though the periods are dropped) for Auto-Immune Deficiency Syndrome. So all four letters are capitalized.
    - Udik 7y ago
      Acquired, not Auto.
    - 7y ago
inam1990 7y ago
Curious ! how cronavirus start with this at first https://boomboomgadgets.de/collections/best-seller/products/gluckliches-haustier-staubsauger?_pos=1&_sid=cb0951361&_ss=r https://boomboomgadgets.de/collections/best-seller/products/...
CrankyBear 7y ago
Nothing but bad news.
lvs 7y ago
If I reduce your load of gunshot wounds near zero but to a nonzero value, the pathogenesis of your disease will still worsen. This blogger will then claim that the gunshot wound hypothesis is flawed! The data shows that reducing amyloid-beta load is not sufficient to confer a clinical benefit. That's all the data shows. The failure of these drugs does not preclude the role of amyloid formation in the diseases. In particular, there is no known dose-response relationship for amyloid-beta or other pathogenically-implicated amyloid proteins. The conclusion is similar: these drugs aiming to reduce amyloid load are illogical. But the subsequent claim that the amyloid hypothesis is wrong does not follow.
- whymauri 7y ago
  I don't believe Derek is denying the role of amyloid formation in Alzheimer's here. Just questioning the efficacy of this particular therapeutic hypothesis. Note that the therapeutic hypothesis and mechanistic hypothesis can co-exist and be slightly disjoint due to the lack of a deeper understanding of the disease. That's how I interpret this post, at least.
- nate_meurer 7y ago
  > The data shows that reducing amyloid-beta load is not sufficient to confer a clinical benefit. No, this trial was designed to test whether preventing amyloid plaque formation can prevent Alzheimer's. To the extent that it does not (which appears to be the conclusion), then it's safe to say that amyloid hypothesis is wrong. In other words, if these patients do not acquire amyloid plaque, but still acquire Alzheimer's at the same rate and severity, then amyloid plaques logically cannot be the cause of Alzheimer's. This should no longer surprise anyone. These studies, coupled with the existence of people who have been found to be loaded with amyloid plaque and yet do NOT get Alzheimers [1], should be plenty to change the direction of research. 1 - https://www.sciencemag.org/news/2019/11/colombian-woman-s-genes-offer-new-clues-staving-alzheimer-s https://www.sciencemag.org/news/2019/11/colombian-woman-s-ge...
alfon 7y ago
I found this old presentation making a set of hypothesis regarding Alz etiology, possible mechanisms and possible treatments somewhat interesting: https://www.youtube.com/watch?v=j1FmK4582mA https://www.youtube.com/watch?v=j1FmK4582mA. I am obviously biased towards this concept, as I have personally seen my mom slow reverse her early dementia with the help of an experimental Mercury removing drug, but since Alzheimer is really only confirmed by Autopsy, and we happen to live close by a Chlor Alkali plant that has been dumping Hg to the environment for decades, we would never know if she would have eventually died / get diagnosed of Alz.
- eyegor 7y ago
  Mercury poisoning can also cause things like memory loss and neuropathy. It seems like a reasonable explanation given your anecdata. https://en.wikipedia.org/wiki/Mercury_poisoning https://en.wikipedia.org/wiki/Mercury_poisoning
  - alfon 7y ago
    Right, although apparently it can as well, at a very low levels cause the same degeneration to neurons as seen in Alzheimer disease, unlike any other heavy metal tested as far as I know. I found this video pretty interesting: https://www.youtube.com/watch?v=XU8nSn5Ezd8 https://www.youtube.com/watch?v=XU8nSn5Ezd8
    - vikramkr 7y ago
      yeah, mercury is dangerous with how toxic it can be at low levels in an organic form. If you have a case for mercury poisoning, is it possible to sue the company responsible via class action lawsuit or the like? Sorry to hear about what you're going through, I hope the drug works and wish you all the best.
ISL 7y ago
As I tell my students all the time -- properly-executed, an experiment that doesn't work is not a failure. If you don't internalize this idea, you will find experimental physics to be psychologically untenable. If you build an experiment (at any scale) to test out an idea that you think is going to work, and it doesn't work, you made progress. Now you know something really essential -- that thing that seemed like a well-motivated idea has some kind of unknown flaw. With that in hand, you can proceed to try something better, whether it is a refined approach or something entirely new. Without doing the experiment, that well-motivated idea would still look like something worth trying. If a large team of people were willing to spend years and lots of resources on an Alzheimer's clinical trial, it was likely to be because they thought it had a real chance of working. If it didn't work, we all benefit from their effort.
- Fr0styMatt88 7y ago
  This is a teaching that really stuck with me from one of my university professors as well. I really wish this was something that was taught more to the general public, I think especially in schools. At least for me, it's something I'd never heard said in a succinct way until I was in university.
  - ImaCake 7y ago
    I wish this idea would sink in for scientists! Academia (my experience is in biological sciences) has a long tradition of hiding negative results and only valuing the rare positive results in a sea of messy data and unexplainable failure.
    - theseadroid 7y ago
      I doubt many scientists don't know this. However the current situation is largely if not all motivated by how funding is provided. Instead of a culture issue, I'd say it's a money issue.
- duxup 7y ago
  I always thought that was sort of the point of the business side of "Fail Fast". Try it now, if it doesn't work, now you know something valuable and you can try something else. As someone who suffers from a lot of analysis paralysis, distraction ... sometimes I find just making myself keep typing and trying things in order to fail quickly and learn from it leads to much faster / sooner successes rather than burying myself up in all the minuta and every aspect of something and... not doing it. There was an old TV show called Connections where they tracked various inventions and progress over history, and IIRC it is telling that almost every positive step they note involve someone failing to do something else they were trying, but still finding out something valuable that adds up to the next step for something else and so on. https://en.wikipedia.org/wiki/Connections_(TV_series) https://en.wikipedia.org/wiki/Connections_(TV_series)
nabla9 7y ago
Spending billions in basic research that investigates the causes of Alzheimer without a potential patentable drug is not economically valuable for private companies. If the cause is found it might not require expensive new drug to cure. This research should be funded by the governments.
- vikramkr 7y ago
  Basic research already is mainly funded by governments. The research in this article is an attempt at a drug being developed by a private company, which is seperate from research that investigates the cause of Alzheimers disease. Once the root cause is discovered, if it somehow needs no drug or device intervention to be treated, then great! Otherwise, the private sector would step in to take those drugs to market and pay for those trials then.
aazaa 7y ago
> I really don’t know what else to say at this point. I’ve been writing this blog since 2002, several years after my own experiences with Alzheimer’s drug discovery, and ever since then I have chronicled the failure of drug after drug aimed at the amyloid hypothesis. Different mechanisms, different dosing, different patient populations, different trial designs: none of it has worked. Not once. I myself include the most recent Biogen/Eisai antibody efforts in that list – yes, the one that they’ve submitted to the FDA and are trying to get approved, a decision about which I have made my position abundantly clear. What's remarkable isn't the failure of this trial, but the complete lack of efficacy for any drug working through the "amyloid hypothesis." https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_disease#Amyloid_hypothesis https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_... Either this hypothesis is completely wrong, or all of the drugs in all of these trials aren't able to address the amyloid. Given the weight of evidence, it seems like there's not much left of the amyloid hypothesis to even poke a hole through.
tylerjwilk00 7y ago
What's the next best guess for a target now that the amyloid hypothesis seems to be a failure?
derefr 7y ago
Something interesting I stumbled upon recently: https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase#Pathology_(aldehyde_dehydrogenase_deficiency) https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase#Patholo... Specifically these quotes: > Some case-control studies claimed that carriage of ALDH2x2 allele was a risk of late-onset Alzheimer's disease independent of the apolipoprotein E gene (the odds for LOAD in carriers of ALDH2x2 allele almost twice that of non-carriers). Moreover, ALDH gene, protein expression and activity are substantially decreased in the substantia nigra of Parkinson's disease patients. These reports are in line with findings implementing toxic lipid oxidation-derived aldehydes in these diseases and in neurodegeneration in general. > The ALDH2-/- mice display age-related memory deficits in various tasks, as well as endothelial dysfunction, brain atrophy, and other Alzheimer's disease-associated pathologies, including marked increases in lipid peroxidation products, amyloid-beta, p-tau and activated caspases. These behavioral and biochemical Alzheimer's disease-like deficits were efficiently ameliorated when the ALDH2-/- mice were treated with isotope-reinforced, deuterated polyunsaturated fatty acids (D-PUFA). D-PUFA is interesting (and being investigated for use in other diseases, e.g. Huntington's) but it's just addressing the proximal cause of the neurodegeneration (= the build-up of peroxidation products in the brain) rather than the mechanism by which those products are produced. I'm much more curious to know whether introduction of exogenous ALDH2 into the body (perhaps above wild-type expressed levels of ALDH2) might be neuroprotective/prophylactic against neurodegenerative disease. As far as I can search, though, nobody's ever even extracted+purified an ALDH2 enzymatic solution, let alone tested it for such effects.
eternalny1 7y ago
Amyloid plaques are clearly not the problem, but I thought we already knew that? When did these experiments get launched? There are people who appear to be genetically immune to Alzheimer's yet build up massive amyloid plaques. They do not show any symptoms of the disease, so shouldn't this have been ruled out by now?
- jcranmer 7y ago
  Looking back through Derek Lowe's posts, I don't think he considered the amyloid hypothesis dead until around 2016 or so. The study was started in December 2012, according the clinicaltrials.gov posting. At that time, you had the first round of amyloid blockers that didn't work, but you were in the midst of the hail-mary round of "maybe it works if you catch it early/in this group of people/etc." tests. Indeed, this is one of those studies.
it 7y ago
This seems quite consistent with the idea that microtubules are the locus of the real action of consciousness and memory. The amyloid theory would then be confusing cause and effect. If that's so, plaques don't cause Alzheimers; they are the side-effect of a process that causes Alzheimers: disintegration of microtubules.

123 points by hprotagonist 7y ago

I have hopes in the ongoing trials by Dean Ornish regarding Alzheimer's. It seems all other common age related health issues are improved by a vegan diet, so it will be interesting to see the results of this study.

wiremine 7y ago

Anyone have any breakdown of what this means for the laymen out here on HN? I get the gist this was a major (but not unpredicted) failure, but am I reading it wrong? Was this for one category of drugs, or a hypothesis about the cause of Alzheimer's in general, or both?

exhilaration 7y ago
There was a good HN discussion a few weeks back about this: https://news.ycombinator.com/item?id=21911225 https://news.ycombinator.com/item?id=21911225 It's becoming increasingly clear that the entire Amyloid-beta plaque hypothesis has been wrong and last 20+ years of Alzheimer's research and drug development has been wasted.
- eganist 7y ago
  Yup, and the infectious theory is the one that's gradually getting more and more mainstream traction (the premise being that beta amyloid has a tactical immune function in the brain but trades short-term success against pathogens at the expense of long term longevity in people who can't clear the plaques out effectively with restful sleep). Good Google scholar queries include 'hsv apoe4' as well as 'gingivitis alzheimers', without quotes, and among others. I can dig up my past comments that went into depth on all the different studies here, but a lot of doctors have yet to be swayed on the new theory. Edit: found a good reference page with all the different trials going on around different theories for Alzheimer's, including the infectious theory. http://www.cumc.columbia.edu/adrc/patients-and-families/clinical-trials http://www.cumc.columbia.edu/adrc/patients-and-families/clin... has all the current trials https://clinicaltrials.gov/ct2/show/NCT03282916 https://clinicaltrials.gov/ct2/show/NCT03282916 is the valacyclovir trial trying to replicate the 2018 results out of Taiwan. A different angle is the recently discussed correlation between lithium intake and Alzheimer's, and that's also being explored: https://clinicaltrials.gov/ct2/show/NCT02129348 https://clinicaltrials.gov/ct2/show/NCT02129348
  - atombender 7y ago
    That clinical trials list doesn't mention the GAIN phase 2/3 trial [1] [2] currently underway to test COR388 from Cortexyme [3]. It's a small molecule that targets gingipains, cysteine proteases of the P. gingivalis, a periodontal pathogen responsible for gingivitis that has been found in Alzheimer's patients. Here [4] is a paper on the gingivalis hypothesis funded by Cortexyme. [1] https://clinicaltrials.gov/ct2/show/NCT03823404?term=NCT03823404&draw=2&rank=1 https://clinicaltrials.gov/ct2/show/NCT03823404?term=NCT0382... [2] https://gaintrial.com/en/about https://gaintrial.com/en/about [3] https://www.cortexyme.com/?page_id=6022 https://www.cortexyme.com/?page_id=6022 [4] https://advances.sciencemag.org/content/5/1/eaau3333 https://advances.sciencemag.org/content/5/1/eaau3333
  - nextos 7y ago
    It's not necessarily pathogens only but it can also be commensal dysbiosis. See the discussion linked by the parent comment or my other comment here. We should start thinking about all diseases that involve the HLA gene and dysfunctional immune responses as autoimmunity. Not just the obvious ones. Hence the question is simply why is the immune system misclassifying our own tissues? It's a CS / information theory problem.
- nextos 7y ago
  Yes. My comment triggered most of that discussion. I have really good solid evidence for another common disease being caused by infection or microbiome dysbiosis. But I am encountering a lot of resistance in the field despite my theory, models and data being much more solid than the status quo to explain said disease and my research coming from a famous lab. I guess it's really hard for lots of people to accept most of their careers were spent chasing the wrong hypothesis. I've reached a tipping point where I think I can only push it further and develop a drug in a startup. Alzheimer's and Parkinson's are also something I want to tackle because the mechanism is analogous. If someone wants to help or some VC is interested, just let me know. Contact email is in my profile. These diseases have a big CS / information theory component.
  - Vomzor 7y ago
    What’s the disease? My personal experience and the research I’ve read makes me believe you are absolutely right.
    - deleted 7y ago
      [deleted]
    - esdott 7y ago
      Probably something like MS or another auto-immune disorder that could be microbiome and/or dopamine related. Could also be type 1 diabetes, RA, Crohn's, etc. Those would be my guess.
    - fernly 7y ago
      No idea if this is nextos's thing, but there's evidence for inflammation as a root cause of depression. cf Bullmore, the Inflamed Mind.
  - vikramkr 7y ago
    What's the disease and what's the resistance from the field? Microbiome stuff isn't as hot an area of investment as it was a few years back, but there's tons of biotech funding to go around (assuming you're in the US) and if you have solid data and an actionable drug, it shouln't be extraordinarily difficult to form a company around it in this economy.
- jdhn 7y ago
  If the past 20 years of research & drug development have been wasted, how does the average person help steer the ship away from clearing the plaque, and more towards identifying and treating the cause of the plaque in the first place?
deleted 7y ago
[deleted]
abhisuri97 7y ago
Kinda both. Increased presence of amyloid (a type of protein) plaques are common in patients with Alzheimer's disease, so it was hypothesized that these plaques contribute to alzheimers. The drugs mentioned specifically targeted these plaques (via monoclonal antibodies). These drugs didn't slow the progression of alzheimers in the patient population that was certain to get it. The drugs could have failed for two reasons I think: 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue) or 2) the amyloid plaques themselves are actually being broken up by the drug...but the plaques may not really be a cause of alzheimers (in which case the hypothesis is the issue).
- jcranmer 7y ago
  > 2) the amyloid plaques themselves are actually being broken up by the drug This is actually what several studies have shown--the amyloid plaques were being removed by the drugs, but the progression of Alzheimer's was not slowed or halted.
  - hprotagonist 7y ago
    Different disease, but if you really want to be depressed: https://blogs.sciencemag.org/pipeline/archives/2017/05/18/now-this-is-a-drug-that-does-not-work https://blogs.sciencemag.org/pipeline/archives/2017/05/18/no...
- n0rbwah 7y ago
  > 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue) Shouldn't it be possible to have a look at the patients brains to see if there's any difference in plaque formation in those that underwent treatment vs those who had the placebo.

downerending 7y ago

tldr: No effect for the two antibodies tested.

streptomycin 7y ago

As that last-linked blog post makes clear, I don’t find that evidence compelling, and most certainly not compelling enough to approve the drug as it stands. But with the way the FDA is behaving these days, God only knows what’s going to happen. People are investing on just that basis, although rarely stated in quite those words. But if you can look at the ruins of all the attempts to show efficacy with anti-amyloid antibody therapies and decide that the Biogen/Eisai data represent a real ray of hope, you have a sunnier disposition than I do. I share the cynicism! Early drugs targeted amyloid plaques because it seemed like a good idea. But after so many failures, I can't think of any reason so much time and money is spent on a failed hypothesis other than hoping for a false positive. Because a false positive, even with very modest results, would result in a ridiculously profitable drug given the complete lack of Alzheimer's treatments we currently have.

melling 7y ago
Because there’s very little money is invested in Alzheimer’s research. People were very conservative in their choices. We were spending a lot more on AIDS research 20 years ago than on Alzheimer’s today: https://www.ncbi.nlm.nih.gov/books/NBK222902/ https://www.ncbi.nlm.nih.gov/books/NBK222902/ This produced great results for AIDS, which many people thought would never be treatable. Anyway, medical research is expensive. Considering the number of people who will get Alzheimer’s and the cost to deal with the disease, you would have thought we’d have been spending more on research for the past several decades. Maybe soon we will all agree that it’s probably worth investing more on research?
- SAI_Peregrinus 7y ago
  FYI, AIDS is an acronym (though the periods are dropped) for Auto-Immune Deficiency Syndrome. So all four letters are capitalized.
  - Udik 7y ago
    Acquired, not Auto.
  - 7y ago

inam1990 7y ago

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CrankyBear 7y ago

Nothing but bad news.

lvs 7y ago

If I reduce your load of gunshot wounds near zero but to a nonzero value, the pathogenesis of your disease will still worsen. This blogger will then claim that the gunshot wound hypothesis is flawed! The data shows that reducing amyloid-beta load is not sufficient to confer a clinical benefit. That's all the data shows. The failure of these drugs does not preclude the role of amyloid formation in the diseases. In particular, there is no known dose-response relationship for amyloid-beta or other pathogenically-implicated amyloid proteins. The conclusion is similar: these drugs aiming to reduce amyloid load are illogical. But the subsequent claim that the amyloid hypothesis is wrong does not follow.

whymauri 7y ago
I don't believe Derek is denying the role of amyloid formation in Alzheimer's here. Just questioning the efficacy of this particular therapeutic hypothesis. Note that the therapeutic hypothesis and mechanistic hypothesis can co-exist and be slightly disjoint due to the lack of a deeper understanding of the disease. That's how I interpret this post, at least.
nate_meurer 7y ago
> The data shows that reducing amyloid-beta load is not sufficient to confer a clinical benefit. No, this trial was designed to test whether preventing amyloid plaque formation can prevent Alzheimer's. To the extent that it does not (which appears to be the conclusion), then it's safe to say that amyloid hypothesis is wrong. In other words, if these patients do not acquire amyloid plaque, but still acquire Alzheimer's at the same rate and severity, then amyloid plaques logically cannot be the cause of Alzheimer's. This should no longer surprise anyone. These studies, coupled with the existence of people who have been found to be loaded with amyloid plaque and yet do NOT get Alzheimers [1], should be plenty to change the direction of research. 1 - https://www.sciencemag.org/news/2019/11/colombian-woman-s-genes-offer-new-clues-staving-alzheimer-s https://www.sciencemag.org/news/2019/11/colombian-woman-s-ge...

alfon 7y ago

I found this old presentation making a set of hypothesis regarding Alz etiology, possible mechanisms and possible treatments somewhat interesting: https://www.youtube.com/watch?v=j1FmK4582mA https://www.youtube.com/watch?v=j1FmK4582mA. I am obviously biased towards this concept, as I have personally seen my mom slow reverse her early dementia with the help of an experimental Mercury removing drug, but since Alzheimer is really only confirmed by Autopsy, and we happen to live close by a Chlor Alkali plant that has been dumping Hg to the environment for decades, we would never know if she would have eventually died / get diagnosed of Alz.

eyegor 7y ago
Mercury poisoning can also cause things like memory loss and neuropathy. It seems like a reasonable explanation given your anecdata. https://en.wikipedia.org/wiki/Mercury_poisoning https://en.wikipedia.org/wiki/Mercury_poisoning
- alfon 7y ago
  Right, although apparently it can as well, at a very low levels cause the same degeneration to neurons as seen in Alzheimer disease, unlike any other heavy metal tested as far as I know. I found this video pretty interesting: https://www.youtube.com/watch?v=XU8nSn5Ezd8 https://www.youtube.com/watch?v=XU8nSn5Ezd8
  - vikramkr 7y ago
    yeah, mercury is dangerous with how toxic it can be at low levels in an organic form. If you have a case for mercury poisoning, is it possible to sue the company responsible via class action lawsuit or the like? Sorry to hear about what you're going through, I hope the drug works and wish you all the best.

ISL 7y ago

As I tell my students all the time -- properly-executed, an experiment that doesn't work is not a failure. If you don't internalize this idea, you will find experimental physics to be psychologically untenable. If you build an experiment (at any scale) to test out an idea that you think is going to work, and it doesn't work, you made progress. Now you know something really essential -- that thing that seemed like a well-motivated idea has some kind of unknown flaw. With that in hand, you can proceed to try something better, whether it is a refined approach or something entirely new. Without doing the experiment, that well-motivated idea would still look like something worth trying. If a large team of people were willing to spend years and lots of resources on an Alzheimer's clinical trial, it was likely to be because they thought it had a real chance of working. If it didn't work, we all benefit from their effort.

Fr0styMatt88 7y ago
This is a teaching that really stuck with me from one of my university professors as well. I really wish this was something that was taught more to the general public, I think especially in schools. At least for me, it's something I'd never heard said in a succinct way until I was in university.
- ImaCake 7y ago
  I wish this idea would sink in for scientists! Academia (my experience is in biological sciences) has a long tradition of hiding negative results and only valuing the rare positive results in a sea of messy data and unexplainable failure.
  - theseadroid 7y ago
    I doubt many scientists don't know this. However the current situation is largely if not all motivated by how funding is provided. Instead of a culture issue, I'd say it's a money issue.
duxup 7y ago
I always thought that was sort of the point of the business side of "Fail Fast". Try it now, if it doesn't work, now you know something valuable and you can try something else. As someone who suffers from a lot of analysis paralysis, distraction ... sometimes I find just making myself keep typing and trying things in order to fail quickly and learn from it leads to much faster / sooner successes rather than burying myself up in all the minuta and every aspect of something and... not doing it. There was an old TV show called Connections where they tracked various inventions and progress over history, and IIRC it is telling that almost every positive step they note involve someone failing to do something else they were trying, but still finding out something valuable that adds up to the next step for something else and so on. https://en.wikipedia.org/wiki/Connections_(TV_series) https://en.wikipedia.org/wiki/Connections_(TV_series)

nabla9 7y ago

Spending billions in basic research that investigates the causes of Alzheimer without a potential patentable drug is not economically valuable for private companies. If the cause is found it might not require expensive new drug to cure. This research should be funded by the governments.

vikramkr 7y ago
Basic research already is mainly funded by governments. The research in this article is an attempt at a drug being developed by a private company, which is seperate from research that investigates the cause of Alzheimers disease. Once the root cause is discovered, if it somehow needs no drug or device intervention to be treated, then great! Otherwise, the private sector would step in to take those drugs to market and pay for those trials then.

aazaa 7y ago

> I really don’t know what else to say at this point. I’ve been writing this blog since 2002, several years after my own experiences with Alzheimer’s drug discovery, and ever since then I have chronicled the failure of drug after drug aimed at the amyloid hypothesis. Different mechanisms, different dosing, different patient populations, different trial designs: none of it has worked. Not once. I myself include the most recent Biogen/Eisai antibody efforts in that list – yes, the one that they’ve submitted to the FDA and are trying to get approved, a decision about which I have made my position abundantly clear. What's remarkable isn't the failure of this trial, but the complete lack of efficacy for any drug working through the "amyloid hypothesis." https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_disease#Amyloid_hypothesis https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_... Either this hypothesis is completely wrong, or all of the drugs in all of these trials aren't able to address the amyloid. Given the weight of evidence, it seems like there's not much left of the amyloid hypothesis to even poke a hole through.

tylerjwilk00 7y ago

What's the next best guess for a target now that the amyloid hypothesis seems to be a failure?

derefr 7y ago

Something interesting I stumbled upon recently: https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase#Pathology_(aldehyde_dehydrogenase_deficiency) https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase#Patholo... Specifically these quotes: > Some case-control studies claimed that carriage of ALDH2x2 allele was a risk of late-onset Alzheimer's disease independent of the apolipoprotein E gene (the odds for LOAD in carriers of ALDH2x2 allele almost twice that of non-carriers). Moreover, ALDH gene, protein expression and activity are substantially decreased in the substantia nigra of Parkinson's disease patients. These reports are in line with findings implementing toxic lipid oxidation-derived aldehydes in these diseases and in neurodegeneration in general. > The ALDH2-/- mice display age-related memory deficits in various tasks, as well as endothelial dysfunction, brain atrophy, and other Alzheimer's disease-associated pathologies, including marked increases in lipid peroxidation products, amyloid-beta, p-tau and activated caspases. These behavioral and biochemical Alzheimer's disease-like deficits were efficiently ameliorated when the ALDH2-/- mice were treated with isotope-reinforced, deuterated polyunsaturated fatty acids (D-PUFA). D-PUFA is interesting (and being investigated for use in other diseases, e.g. Huntington's) but it's just addressing the proximal cause of the neurodegeneration (= the build-up of peroxidation products in the brain) rather than the mechanism by which those products are produced. I'm much more curious to know whether introduction of exogenous ALDH2 into the body (perhaps above wild-type expressed levels of ALDH2) might be neuroprotective/prophylactic against neurodegenerative disease. As far as I can search, though, nobody's ever even extracted+purified an ALDH2 enzymatic solution, let alone tested it for such effects.

eternalny1 7y ago

Amyloid plaques are clearly not the problem, but I thought we already knew that? When did these experiments get launched? There are people who appear to be genetically immune to Alzheimer's yet build up massive amyloid plaques. They do not show any symptoms of the disease, so shouldn't this have been ruled out by now?

jcranmer 7y ago
Looking back through Derek Lowe's posts, I don't think he considered the amyloid hypothesis dead until around 2016 or so. The study was started in December 2012, according the clinicaltrials.gov posting. At that time, you had the first round of amyloid blockers that didn't work, but you were in the midst of the hail-mary round of "maybe it works if you catch it early/in this group of people/etc." tests. Indeed, this is one of those studies.

it 7y ago

This seems quite consistent with the idea that microtubules are the locus of the real action of consciousness and memory. The amyloid theory would then be confusing cause and effect. If that's so, plaques don't cause Alzheimers; they are the side-effect of a process that causes Alzheimers: disintegration of microtubules.