7 ms·

Exciting work, but mouse models of alzheimers are uniquely bad, even among mouse models. Mice don't get alzheimers, and the mechanisms by which we induce alzhei

Exciting work, but mouse models of alzheimers are uniquely bad, even among mouse models. Mice don't get alzheimers, and the mechanisms by which we induce alzheimers-like conditions in mice are not analogous to human alzheimers. This model, 5xfad, overexpresses app and psen1, which is not how human alzheimers works[0]. So basically, we give mice a different disease that happens to looks like alzheimers, then cure that disease, and hope that the cure somehow transfers to real alzheimers, which (like cancer) may not even end up being one well defined disease. There's some work on developing organoids and other models that will hopefully allow us to have better luck with this disease space in the future, but until then, we don't have good models. Take any research in mice in neurodegeneration with an even bigger grain of salt than other diseases. However, the mechanism found here is certainly very cool, and the neurological/mechanistic research is pretty interesting. Just don't have expectations of this directly translating into a successful drug development process - the mechanistic insights of the gene they studies are fascinating and worthy research on their own to increase our understanding of neural proteins and their functions. [0]https://www.nature.com/articles/d41586-018-05722-9 https://www.nature.com/articles/d41586-018-05722-9

PaulAJ 6y ago
This is true, sad to say. "Big new discovery about Altzheimer's Disease (in mice)" is pretty much on a par with "Amazing new battery (in lab)". You see articles like this a couple of times a year, but they never pan out. Thats not to say that this research isn't worth-while, just don't expect it to turn into a cure for humans.
- vikramkr 6y ago
  Its like cancer research in the 70s. Lots of money focused on a couple of areas of drug development (like chemo), but the real progress is going to come from long term, deep mechanistic research. We spent so much money on cancer treatments in the 70s, but the real impact came from the work that slowly revealed the underpinnings of cancer as a genetic disease as well as the development of new modalities of treatment (immunotherapy) that paid massive dividends down the line. In the same way, I think we need deeper fundamental understandings of the disease, and that combining those with the explosion in new treatment modalities we've seen over the past two decades (e.g. cell and gene therapies etc.) Is whats going to get us over the finish line. Until then, might as well keep throwing immunotherapies at whatever targets we find hoping one of them will stick, the same way we did cancer research with small molecules decades ago.
  - SubiculumCode 6y ago
    But both were definitely worth while. No doubt chemo has saved/extended lines, and most likely a winnable research goal in the short term, while the investments needed (e.g. immuno/genetic therapy and etiologies, was simply beyond the near term capabilities of science in the 70's.
- oivey 6y ago
  Even the battery comparison is generous because improvements in battery tech actually have made it out of the lab and into consumer products. Further, a lab battery actually functions as a battery, whereas a cure for fake mouse Alzheimer’s is several steps away from being proven as a cure for human Alzheimer’s. Alzheimer’s research is more like research into room temperature superconductors. No one has proven that what they’re seeking is even possible, but it sure would be nice.
  - jagraff 6y ago
    Not to comment on Alzheimer's research, but room temperature superconductors have proven to be possible (and have been created in a lab) - https://www.nature.com/articles/s41586-020-2801-z https://www.nature.com/articles/s41586-020-2801-z However, they haven't yet found one that can also exist at atmospheric pressure.
- shoo 6y ago
  also: > "In a diamond anvil" is the "in mice" of superconductivity. -- Tade0 https://news.ycombinator.com/item?id=24781607 https://news.ycombinator.com/item?id=24781607 less seriously, what if we permuted the qualifiers: "big new discovery about altzheimer's disease (in a diamond anvil)" "amazing new battery (in mice)"
  - taneq 6y ago
    New technique cures cancer in batteries?
    - TeMPOraL 6y ago
      New diamond anvil cures batteries in a Petri dish. Oh wait, this actually parses into something that could plausibly mean something sensible...
  - mattkrause 6y ago
    The aptly-named @JustSaysInMice Twitter account does exactly that! https://twitter.com/justsaysinmice https://twitter.com/justsaysinmice
lebuffon 6y ago
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.
raducu 6y ago
Why don't we use apes instead? Too long lifespan?
- qppo 6y ago
  Or how about people? I have family suffering from the disease and if I develop it, I want to be experimented on. It's not like I'll have the mental capacity to comprehend or remember most of it.
  - hmahncke 6y ago
    Join a clinical trial here (organized by the Alzheimer's Association): https://www.alz.org/alzheimers-dementia/investigacion/ensayos-clinicos/about-clinical-trials https://www.alz.org/alzheimers-dementia/investigacion/ensayo... Speaking as a researcher in this field, more people willing to volunteer for clinical trials is incredibly important.
  - vikramkr 6y ago
    We've got tons of clinical trials going on. None of them have worked so far, but nevertheless, we spend billions experimenting on humans, and trials are always looking for volunteers
- vikramkr 6y ago
  Lifespan is a general problem with aging disorders. These studies take forever to run and cost so much, but we pour the money in anyway. Theres definitely some work with nonhuman primates - but with the brain no model is really that great. I mean, it's not surprising, our brain is kind of our defining characteristic as a species. Though with organoids made from our brain tissue, maybe we'll have better luck.
- ajarmst 6y ago
  Another issue is that evaluating memory disorders like AD is really hard if your subjects don't have language and can't discuss their subjective experience. A mouse that can still find its way around a maze that it learned is hard to compare to a person that can still find their way to their office but can't remember colleagues' names or whether they are married. Apes wouldn't help with the problem that AD symptoms are tied up with relationships and experiences unique to the only species that has language. (Side note: as someone approaching retirement from a family with a strong history of AD, I'm not entirely sure that the unique faculty of language is worth its associated cost: that we're the only species whose members know they will senesce and die,) Edit: shit, that's maudlin. Need a drink. Ignore me.
caycep 6y ago
I think this article is meant more for potential donors to the university rather than other scientists...
- ajarmst 6y ago
  Another possibility is that someone's tenure committee is meeting soon. :-). I don't want to deride what looks like good primary research, but this release smells of ulterior motives. (˜˜NB: I happen to live in the same province as the sponsoring institution. We've a new government that has made significant cuts to postsecondary and medical funding, and have signalled a desire to do more. I get why they might need to do stuff like this.)
  - caycep 6y ago
    In Canada?! ouch...
    - ajarmst 6y ago
      https://en.wikipedia.org/wiki/Jason_Kenney https://en.wikipedia.org/wiki/Jason_Kenney. Unfortunately, Trump is a symptom of a worldwide phenomena, at least amongst western democracies. Vote wisely.
gorkish 6y ago
Given the statements made in the article, it would seem rather straightforward to look at the incidence of ADRD in the population of existing carvedilol patients. I would think such a thing would precede even a model study, and it's interesting there was no mention of such research. Knowing basically nothing of how such data might be collected or kept, is this trivial or stupidly difficult?
- Smoosh 6y ago
  I thought along similar lines, but apparently they are using a particular variant of the drug, which I assume is not the one regularly prescribed currently.
ajarmst 6y ago
Thanks very much for the caution (reports where the quote about revolutionary results comes from the lead author tend to trigger my skepticism reflex). Looking at the paper, a lot of the results are based on cell studies, in addition to the rodent studies. The research looks good and promising, but it also appears to be incremental progress based on work that's been going on for a decade or so. My other concern is that the racemic form of the drug in question is a popular beta-blocker (the R- isomer alone does appear to have a different physiological effect, it is also apparently a promising arrhythmia drug.) That would indicate to me that there are already probably an awful lot of AD patients taking the racemic mixture regularly. I'd think if it were a miracle drug, we'd probably have at least some indications. Finally, the title of the paper includes the phrase "but [does not prevent] β-Amyloid Accumulation", which seems to directly contradict this marketing release's claim about reversing AD. That said, if they do come up with something that can significantly ameliorate AD symptoms for a decade or so, I'll happily dance in the streets.

PaulAJ 6y ago

This is true, sad to say. "Big new discovery about Altzheimer's Disease (in mice)" is pretty much on a par with "Amazing new battery (in lab)". You see articles like this a couple of times a year, but they never pan out. Thats not to say that this research isn't worth-while, just don't expect it to turn into a cure for humans.

vikramkr 6y ago
Its like cancer research in the 70s. Lots of money focused on a couple of areas of drug development (like chemo), but the real progress is going to come from long term, deep mechanistic research. We spent so much money on cancer treatments in the 70s, but the real impact came from the work that slowly revealed the underpinnings of cancer as a genetic disease as well as the development of new modalities of treatment (immunotherapy) that paid massive dividends down the line. In the same way, I think we need deeper fundamental understandings of the disease, and that combining those with the explosion in new treatment modalities we've seen over the past two decades (e.g. cell and gene therapies etc.) Is whats going to get us over the finish line. Until then, might as well keep throwing immunotherapies at whatever targets we find hoping one of them will stick, the same way we did cancer research with small molecules decades ago.
- SubiculumCode 6y ago
  But both were definitely worth while. No doubt chemo has saved/extended lines, and most likely a winnable research goal in the short term, while the investments needed (e.g. immuno/genetic therapy and etiologies, was simply beyond the near term capabilities of science in the 70's.
oivey 6y ago
Even the battery comparison is generous because improvements in battery tech actually have made it out of the lab and into consumer products. Further, a lab battery actually functions as a battery, whereas a cure for fake mouse Alzheimer’s is several steps away from being proven as a cure for human Alzheimer’s. Alzheimer’s research is more like research into room temperature superconductors. No one has proven that what they’re seeking is even possible, but it sure would be nice.
- jagraff 6y ago
  Not to comment on Alzheimer's research, but room temperature superconductors have proven to be possible (and have been created in a lab) - https://www.nature.com/articles/s41586-020-2801-z https://www.nature.com/articles/s41586-020-2801-z However, they haven't yet found one that can also exist at atmospheric pressure.
shoo 6y ago
also: > "In a diamond anvil" is the "in mice" of superconductivity. -- Tade0 https://news.ycombinator.com/item?id=24781607 https://news.ycombinator.com/item?id=24781607 less seriously, what if we permuted the qualifiers: "big new discovery about altzheimer's disease (in a diamond anvil)" "amazing new battery (in mice)"
- taneq 6y ago
  New technique cures cancer in batteries?
  - TeMPOraL 6y ago
    New diamond anvil cures batteries in a Petri dish. Oh wait, this actually parses into something that could plausibly mean something sensible...
- mattkrause 6y ago
  The aptly-named @JustSaysInMice Twitter account does exactly that! https://twitter.com/justsaysinmice https://twitter.com/justsaysinmice

lebuffon 6y ago

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.

raducu 6y ago

Why don't we use apes instead? Too long lifespan?

qppo 6y ago
Or how about people? I have family suffering from the disease and if I develop it, I want to be experimented on. It's not like I'll have the mental capacity to comprehend or remember most of it.
- hmahncke 6y ago
  Join a clinical trial here (organized by the Alzheimer's Association): https://www.alz.org/alzheimers-dementia/investigacion/ensayos-clinicos/about-clinical-trials https://www.alz.org/alzheimers-dementia/investigacion/ensayo... Speaking as a researcher in this field, more people willing to volunteer for clinical trials is incredibly important.
- vikramkr 6y ago
  We've got tons of clinical trials going on. None of them have worked so far, but nevertheless, we spend billions experimenting on humans, and trials are always looking for volunteers
vikramkr 6y ago
Lifespan is a general problem with aging disorders. These studies take forever to run and cost so much, but we pour the money in anyway. Theres definitely some work with nonhuman primates - but with the brain no model is really that great. I mean, it's not surprising, our brain is kind of our defining characteristic as a species. Though with organoids made from our brain tissue, maybe we'll have better luck.
ajarmst 6y ago
Another issue is that evaluating memory disorders like AD is really hard if your subjects don't have language and can't discuss their subjective experience. A mouse that can still find its way around a maze that it learned is hard to compare to a person that can still find their way to their office but can't remember colleagues' names or whether they are married. Apes wouldn't help with the problem that AD symptoms are tied up with relationships and experiences unique to the only species that has language. (Side note: as someone approaching retirement from a family with a strong history of AD, I'm not entirely sure that the unique faculty of language is worth its associated cost: that we're the only species whose members know they will senesce and die,) Edit: shit, that's maudlin. Need a drink. Ignore me.

caycep 6y ago

I think this article is meant more for potential donors to the university rather than other scientists...

ajarmst 6y ago
Another possibility is that someone's tenure committee is meeting soon. :-). I don't want to deride what looks like good primary research, but this release smells of ulterior motives. (˜˜NB: I happen to live in the same province as the sponsoring institution. We've a new government that has made significant cuts to postsecondary and medical funding, and have signalled a desire to do more. I get why they might need to do stuff like this.)
- caycep 6y ago
  In Canada?! ouch...
  - ajarmst 6y ago
    https://en.wikipedia.org/wiki/Jason_Kenney https://en.wikipedia.org/wiki/Jason_Kenney. Unfortunately, Trump is a symptom of a worldwide phenomena, at least amongst western democracies. Vote wisely.

gorkish 6y ago

Given the statements made in the article, it would seem rather straightforward to look at the incidence of ADRD in the population of existing carvedilol patients. I would think such a thing would precede even a model study, and it's interesting there was no mention of such research. Knowing basically nothing of how such data might be collected or kept, is this trivial or stupidly difficult?

Smoosh 6y ago
I thought along similar lines, but apparently they are using a particular variant of the drug, which I assume is not the one regularly prescribed currently.

ajarmst 6y ago

Thanks very much for the caution (reports where the quote about revolutionary results comes from the lead author tend to trigger my skepticism reflex). Looking at the paper, a lot of the results are based on cell studies, in addition to the rodent studies. The research looks good and promising, but it also appears to be incremental progress based on work that's been going on for a decade or so. My other concern is that the racemic form of the drug in question is a popular beta-blocker (the R- isomer alone does appear to have a different physiological effect, it is also apparently a promising arrhythmia drug.) That would indicate to me that there are already probably an awful lot of AD patients taking the racemic mixture regularly. I'd think if it were a miracle drug, we'd probably have at least some indications. Finally, the title of the paper includes the phrase "but [does not prevent] β-Amyloid Accumulation", which seems to directly contradict this marketing release's claim about reversing AD. That said, if they do come up with something that can significantly ameliorate AD symptoms for a decade or so, I'll happily dance in the streets.