5 ms·

I know nothing about this area but this statement; "...the progression of Alzheimer’s disease is driven by a vicious cycle of the protein amyloid β (Aβ) induci

I know nothing about this area but this statement; "...the progression of Alzheimer’s disease is driven by a vicious cycle of the protein amyloid β (Aβ) inducing hyperactivity at the neuron level." makes me ask wouldn't it be valuable to know what triggers this change from normal activity to hyperactivity? The use of this drug treatment should it even be effective to your point seems a bit like insulin. It keeps the patient alive but doesn't find the root cause. Perhaps I expect too much from biological science at this stage of our development.

vikramkr 6y ago
The statement you quoted should not have been stated so confidently in the article. That statement is the "amyloid hypothesis," and is approximately the equivalent of saying "computer scientists have conclusively determined that tabs are superior to spaces." Basically, you'll start a flame war (although one with more societal importance than tabs vs spaces). Here is an article with a relatively neutral take on it: [0] At a basic level, it seems very likely that alzheimers is a spectrum disease with multiple driving causes, so trying to lump it all under one mechanism of action is probably not the best move anyway. So without going too far into flame war territory (read [1] for a more flamey perspective that I strongly agree with - I won't pretend to be unbiased here), let's just say that from my perspective, articles to the public should not be blindly citing the amyloid hypothesis without contextualizing the controversy and billions of dollars of failed r&d spending in the space chasing a result. [0] https://www.nature.com/articles/d41586-018-05719-4 https://www.nature.com/articles/d41586-018-05719-4 [1] https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte...
- btilly 6y ago
  You avoided the flames, but I won't. The amyloid beta hypothesis is the result of a failure to understand that correlation does not imply causation. As a result an entire field of science has been taken over by people who are convinced that the correlation between Alzheimer's and amyloid plaques in the brain is proof of causation. When attempts to treat people on the basis of this theory failed, they doubled down on the theory rather than questioning their reasoning. The result has been decades of failure and suppression of all alternate lines of research. As a result, billions of dollars have been spent researching only one idea. Which means that the arrival of effective medications has been delayed by a generation. Or possibly two. As a result of which, each year we spend hundreds of billions of dollars treating the tragedy of millions of Americans living with dementia. Most of whom likely would not have dementia today if alternate lines of research had been allowed to flourish decades ago. There are some pieces of stupidity that we should be allowed to get angry about. Here is a comparison. The number of people trapped in misery RIGHT NOW from Alzheimer's is a multiple of how many Americans would be projected to die if we all caught COVID-19 right now and nobody got treatment. But Alzheimer's happens in slow motion and there is no public awareness of the size of the debacle. So only a small fringe gets upset about it. Personal note. About 20 years ago I got interested in the topic, and concluded all of what I just said. However I'm not in medical research, and even if I was it would have been impossible to get funding for researching the myriad of root causes that had not been investigated. I didn't learn anything that added to this picture until 2 years ago. That is when articles came out identifying that infection appears to have a causal relationship (rather than the mere correlation of amyloid plaques), and people became aware of research demonstrating that anti-viral drugs can reduce the rate of Alzheimer's by 80%. Now for evidence that adherence to theory really did cost us a generation. As https://blogs.scientificamerican.com/observations/could-alzheimers-be-a-reaction-to-infection/ https://blogs.scientificamerican.com/observations/could-alzh... points out, the correlation between HIV-1 and Alzheimer's was demonstrated in 1997. Clinical research demonstrating the anti-virals help with Alzheimer's came out in 2011. Both results sank without a trace for years. By contrast if people studying Alzheimer's had the intellectual honesty to keep saying that amyloid plaques are only shown to be correlated with Alzheimer's, then the 1997 research would have likely spurred follow-up research faster. And the positive 2011 result would have resulted in adoption much faster. But instead they dishonestly doubled down through decades of failure. And effective prophylactic treatments THAT ALREADY EXIST won't be likely to become common medical practice for many years to come. How many more lives are being destroyed every day due to this ongoing stupidity? Basic epistemological mistakes have consequences. The consequences of this one are staggering.
  - vikramkr 6y ago
    Well, I didn't avoid the flames entirely. I singed myself a bit with the second article I linked. You might enjoy it if you haven't already read it
    - btilly 6y ago
      I have read it, but I still enjoyed re-reading it. My interest in the subject was sparked some 20 years ago when I ran across an article about how people who question the amyloid hypothesis were being shut out of academia. I read up on it, drew the conclusions that I described above, then filed it away. My gratification at having come to the right conclusion then doesn't match my annoyance that collective groupthink in the field has cost us collectively so much.
      - vikramkr 6y ago
        Don't worry, we have now identified tau tangles. This must be the root cause, since it is unfathomable that a complex neurodegenerative disease could have complex causes. Now that we have identified [insert misfolded protein candidate here], we can finally create a mouse models with the protein broken, then fix the protein, and then announce a cure. /s Just so that this comment has something constructive in it - I'll add that I think it's important to understand that scientists are human and are also drawn by the allure of oversimple explanations for complex issues. For alzheimers, of the cause was a single protein or gene or something we already understand, we would have found it already. This isn't some ultra rare disease where nobody is looking. Its hard to say "I dont know," but that's the truth. The answer to this is going to come out of some obscure basic research that doesn't even seem obviously tied to neurology yet - and whatever team is working on it is going to have no idea how important their work is and is still going to get a great "I told you so!" moment out of it with regards to all the people asking them if their research has any practical purpose right now.
  - breck 6y ago
    > However I'm not in medical research, and even if I was it would have been impossible to get funding for researching the myriad of root causes Having been a software engineer my whole career and then spending a few years in cancer research, I can tell you there is a big shortage/demand for senior software engineers and there are many funded PIs open to bringing on senior engineers to direct their own projects. I'd encourage you to take a look as we need more good people!
- gorkish 6y ago
  I agree the statement in the article regarding amyloid strikes me more as journalistic framing and makes me think the author isn't quite up to speed on AD research today. The paper in question [0] states front and center that they do not see a change in beta amyloid accumulation in this study. [0] https://www.cell.com/cell-reports/pdf/S2211-1247(20)31158-X.pdf https://www.cell.com/cell-reports/pdf/S2211-1247(20)31158-X....
xkcd-sucks 6y ago
Receptor dysfunction in AD brains has been an active topic of research for decades, and most of the drugs approved for treating AD (NMDA antagonists, cholinesterase inhibitors) modulate neuronal activity.

vikramkr 6y ago

The statement you quoted should not have been stated so confidently in the article. That statement is the "amyloid hypothesis," and is approximately the equivalent of saying "computer scientists have conclusively determined that tabs are superior to spaces." Basically, you'll start a flame war (although one with more societal importance than tabs vs spaces). Here is an article with a relatively neutral take on it: [0] At a basic level, it seems very likely that alzheimers is a spectrum disease with multiple driving causes, so trying to lump it all under one mechanism of action is probably not the best move anyway. So without going too far into flame war territory (read [1] for a more flamey perspective that I strongly agree with - I won't pretend to be unbiased here), let's just say that from my perspective, articles to the public should not be blindly citing the amyloid hypothesis without contextualizing the controversy and billions of dollars of failed r&d spending in the space chasing a result. [0] https://www.nature.com/articles/d41586-018-05719-4 https://www.nature.com/articles/d41586-018-05719-4 [1] https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte...

btilly 6y ago
You avoided the flames, but I won't. The amyloid beta hypothesis is the result of a failure to understand that correlation does not imply causation. As a result an entire field of science has been taken over by people who are convinced that the correlation between Alzheimer's and amyloid plaques in the brain is proof of causation. When attempts to treat people on the basis of this theory failed, they doubled down on the theory rather than questioning their reasoning. The result has been decades of failure and suppression of all alternate lines of research. As a result, billions of dollars have been spent researching only one idea. Which means that the arrival of effective medications has been delayed by a generation. Or possibly two. As a result of which, each year we spend hundreds of billions of dollars treating the tragedy of millions of Americans living with dementia. Most of whom likely would not have dementia today if alternate lines of research had been allowed to flourish decades ago. There are some pieces of stupidity that we should be allowed to get angry about. Here is a comparison. The number of people trapped in misery RIGHT NOW from Alzheimer's is a multiple of how many Americans would be projected to die if we all caught COVID-19 right now and nobody got treatment. But Alzheimer's happens in slow motion and there is no public awareness of the size of the debacle. So only a small fringe gets upset about it. Personal note. About 20 years ago I got interested in the topic, and concluded all of what I just said. However I'm not in medical research, and even if I was it would have been impossible to get funding for researching the myriad of root causes that had not been investigated. I didn't learn anything that added to this picture until 2 years ago. That is when articles came out identifying that infection appears to have a causal relationship (rather than the mere correlation of amyloid plaques), and people became aware of research demonstrating that anti-viral drugs can reduce the rate of Alzheimer's by 80%. Now for evidence that adherence to theory really did cost us a generation. As https://blogs.scientificamerican.com/observations/could-alzheimers-be-a-reaction-to-infection/ https://blogs.scientificamerican.com/observations/could-alzh... points out, the correlation between HIV-1 and Alzheimer's was demonstrated in 1997. Clinical research demonstrating the anti-virals help with Alzheimer's came out in 2011. Both results sank without a trace for years. By contrast if people studying Alzheimer's had the intellectual honesty to keep saying that amyloid plaques are only shown to be correlated with Alzheimer's, then the 1997 research would have likely spurred follow-up research faster. And the positive 2011 result would have resulted in adoption much faster. But instead they dishonestly doubled down through decades of failure. And effective prophylactic treatments THAT ALREADY EXIST won't be likely to become common medical practice for many years to come. How many more lives are being destroyed every day due to this ongoing stupidity? Basic epistemological mistakes have consequences. The consequences of this one are staggering.
- vikramkr 6y ago
  Well, I didn't avoid the flames entirely. I singed myself a bit with the second article I linked. You might enjoy it if you haven't already read it
  - btilly 6y ago
    I have read it, but I still enjoyed re-reading it. My interest in the subject was sparked some 20 years ago when I ran across an article about how people who question the amyloid hypothesis were being shut out of academia. I read up on it, drew the conclusions that I described above, then filed it away. My gratification at having come to the right conclusion then doesn't match my annoyance that collective groupthink in the field has cost us collectively so much.
    - vikramkr 6y ago
      Don't worry, we have now identified tau tangles. This must be the root cause, since it is unfathomable that a complex neurodegenerative disease could have complex causes. Now that we have identified [insert misfolded protein candidate here], we can finally create a mouse models with the protein broken, then fix the protein, and then announce a cure. /s Just so that this comment has something constructive in it - I'll add that I think it's important to understand that scientists are human and are also drawn by the allure of oversimple explanations for complex issues. For alzheimers, of the cause was a single protein or gene or something we already understand, we would have found it already. This isn't some ultra rare disease where nobody is looking. Its hard to say "I dont know," but that's the truth. The answer to this is going to come out of some obscure basic research that doesn't even seem obviously tied to neurology yet - and whatever team is working on it is going to have no idea how important their work is and is still going to get a great "I told you so!" moment out of it with regards to all the people asking them if their research has any practical purpose right now.
- breck 6y ago
  > However I'm not in medical research, and even if I was it would have been impossible to get funding for researching the myriad of root causes Having been a software engineer my whole career and then spending a few years in cancer research, I can tell you there is a big shortage/demand for senior software engineers and there are many funded PIs open to bringing on senior engineers to direct their own projects. I'd encourage you to take a look as we need more good people!
gorkish 6y ago
I agree the statement in the article regarding amyloid strikes me more as journalistic framing and makes me think the author isn't quite up to speed on AD research today. The paper in question [0] states front and center that they do not see a change in beta amyloid accumulation in this study. [0] https://www.cell.com/cell-reports/pdf/S2211-1247(20)31158-X.pdf https://www.cell.com/cell-reports/pdf/S2211-1247(20)31158-X....

xkcd-sucks 6y ago

Receptor dysfunction in AD brains has been an active topic of research for decades, and most of the drugs approved for treating AD (NMDA antagonists, cholinesterase inhibitors) modulate neuronal activity.