Research team discovers breakthrough with potential to reverse Alzheimer's
news.ucalgary.ca
news.ucalgary.ca
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.
Thats not to say that this research isn't worth-while, just don't expect it to turn into a cure for humans.
However, they haven't yet found one that can also exist at atmospheric pressure.
> "In a diamond anvil" is the "in mice" of superconductivity. -- Tade0 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)"
Oh wait, this actually parses into something that could plausibly mean something sensible...
"...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.
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
[1] https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte...
[0] https://www.cell.com/cell-reports/pdf/S2211-1247(20)31158-X....
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-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.
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!
A key challenge in biology now is the huge amount of data and wrangling that requires smart software, so someone with strong software engineering skills can be the difference between publishing a paper in 3 months vs 3 years. If you search any of the many top tier bio research orgs (Allen, MD Anderson, Broad) in the USA you'll see lots of openings for software engineers without too much consideration for prior bio experience.
Yes, correlation is suggestive of causation. Yes, it suggests an often fruitful line of research. But while pursuing that line of research it is important to remain aware that it isn't proof. And to not shut off other lines of research.
In this light, it is worth reading http://calteches.library.caltech.edu/51/2/CargoCult.htm again. Science isn't supposed to be easy. Scientists have had to learn the hard way how to be honest with themselves. Some fields have done better on that than others.
Medicine's record on this front has generally been abysmal. And their failure to be honest with themselves about the limits of their own theories in this case has had an opportunity cost measured in trillions of dollars spent on millions of tragically preventable lingering deaths.
In the face of that, it is wrong to argue that their mistake was a defensible jump in reasoning that people shouldn't be blamed for. Instead we should notice that a logical error really can have a cost measured in trillions spent on millions of tragically preventable deaths. And figure out how to not do that again.
Their conclusion? Most ARE doing Cargo Cult Science. Particularly those working in psychology and medical research.
Let that sink in. Because it really, really matters. And given that it is true, perhaps you should stop objecting to the characterization and start thinking about what would be required for that to no longer be true.
Now you said, If you think that more research dollars should go to the second group (and I would likely agree), cool. Well, that is a mild version of what I am saying. I am saying that the decades long refusal of the field to fund or allow publication of any alternative lines of research is a genocidal crime. I mean that quite literally. They wasted billions of dollars entrusted to them and caused millions of unnecessary deaths.
This is not to say that amyloid research should not have been pursued. It was the leading hypothesis for good reason. But doctors have learned the hard way the importance of giving both a diagnosis and a differential. And then to look for evidence for the differential.
Researchers need to be better at doing the same thing. And as long as they are apathetic or, as you have been, openly hostile to it, they will continue doing Cargo Cult science. No matter how impressive the procedure looks, they are failing to do the basic things that are likely to make it work.
Your reference to Metascience is a red herring. Ionnides didn't conclude that basic logic errors were the problem: his focus was on reproducibility and statistical errors as well as problems in experimental design (probably publication of negative results as well, I can't remember). Further, 'Why Most Published Research Findings Are False' was published fifteen years ago. It's mainstream science now, and researchers are entirely aware of it. Feel free to charge (with evidence) that it's being ignored in experimental design, but it's certainly neither controversial nor obscure. It shows up in High School science curricula. Hell, I've used it in freshman college maths.
Feynman and Ionnides focus on experimental design, evidence selection, researcher bias or incompetence in selecting results, and publication of results. They don't say that you can't use correlation as evidence: the problem is not that there's too much evidence being accepted, but that there's too little.
Had you opened with - "they're ignoring evidence they're wrong" or - "this paper has twice failed in replication attempts" or - "the study has too few subjects / no control group / too much noise to accurately measure these weak results" or even went all Smolin with - "the entire research program is based on inadequate and uncritical investigations into a poorly defined and contradictorily applied hypothesis",
I'd be merrily mashing the up arrow. But you opened with "The amyloid beta hypothesis is the result of a failure to understand that correlation does not imply causation." You're asserting that hundreds of thousands of qualified medical researchers don't understand a fundamental principle of the scientific method.
Somewhat amusingly, the published results that prompted this particular discussion is good evidence against the plaque hypothesis (well, it will be after replication and a supporting metastudy). From a well-regarded researcher. I guess they're not all participating in the genocide.
I'm not "hostile" to the idea that AD research might have been misguided or even criminally wasteful of resources. I'm hostile to the assertion that the very close correlation between plaques and AD should not be guiding research and that it is clearly not only wrong but can be easily so demonstrated.
Here are some examples. When I was growing up in the 1980s, we were taught ancient history like how much doctors resisted the idea of handwashing. Those who were curious could learn about the struggle to get double blind studies, and past disasters like the adoption of frontal lobotomies, or the development of hyper-radical mastectomies based on the theory that cancer spread slowly through tissues. (Breast cancer cells actually get metastasized through the blood.) I was so curious, and learned that we do better now.
Except that in the 1990s we found out that millions had had false memories implanted through bad therapy, and the idea of evidence based medicine became mainstream, clarifying how much better we didn't actually do in the 1980s. Under Bill Clinton we even briefly had a committee created to identify the most egregiously ineffective treatments to save costs. That committee's first recommendation was that except in obvious critical trauma cases, back surgery be a last resort to be tried after every other treatment option. The reason why was that it was the most expensive option, was the least likely to be effective, and long-term outcomes were worst.
Sadly, back surgeons were more effective at politics than at treating back pain. (They are also very profitable for hospitals.) Therefore that was also the committee's last report, and it sank without a trace. According to https://www.beckersspine.com/spine/item/45273-surgeons-perfo... reports we do roughlyt 1.6 million back surgeries per year, despite the fact that we have long had evidence indicating that we should do fewer of them. Let's state that a different way. Each year we spend billions of dollars on making the lives of over a million people worse because there is no willingness to act on data that has been available for decades.
THAT is the state of modern medicine.
Oh, and the much hyped move towards evidence based medicine? Every doctor will tell you that we now engage in evidence based medicine, the bad old days are gone. But estimates are that only half of medical procedures that we do have evidence of effectiveness. See https://www.vox.com/the-big-idea/2017/12/28/16823266/medical... for a popular article on that. It also shows that back surgeons have a lot of company. I guess things are better. We have some idea of how much current medical practice is useless..we just aren't doing anything about it.
Now do you see why I don't accept that things have fundamentally gotten better?
Now back to Alzheimer's.
Until less than 3 years ago, the field was openly hostile to research and researchers that didn't accept the amyloid hypothesis. This changed not because the field internally realized that it was doing anything wrong, but because of criticism received from outside the field. In Nature no less. So despite their theoretical awareness of how to do science, they failed to connect that to their own practice.
How many other fields are making similar mistakes but simply haven't been called out on it? My best estimate is, "A lot."
And yes, I did overstate my case in the passage you quoted. A more accurate statement is, "The unquestioned dominance of the amyloid beta hypothesis is the result of a failure to understand that correlation does not imply causation." As I have said repeatedly, there was nothing bad about following up on lines of evidence suggesting that amyloid beta was a good lead. The problem was rejecting all research into ideas that might question the favorite theory.
You know some other examples of where medicine went astray because people involved in a field rejected research into ideas that might question practitioners favored theory? Let's see. Frontal lobotomies, radical mastectomies, repressed memory therapy, back surgery, knee surgery, and so on.
At what point in this list should we start to suspect that there might be a pattern?
It’s more that the AZ field has found this particular correlation over and over and over again. Despite millions (possibly closing in on billions) of dollars, however, it’s proven difficult to turn it into a causal link. A-Beta antibodies repeatedly fail, both before and after the plaques appear. Various types of inhibitors don’t work. If a method does something to amyloids, someone has probably tried it already, often in an expensive and ill-advised trial. This is only barely hyperbolic: https://blogs.sciencemag.org/pipeline/archives/2018/06/12/an...
Oh, we're definitely into billions. Per year, and not total over time.
This year alone, the NIH is spending $2.8 billion on Alzheimer's research. And they are not the only source of research money.
Almost all of that goes to research based on the amyloid hypothesis.
https://www.nia.nih.gov/sites/default/files/2019-07/FY21-NIA...
That's still far too much being thrown into a theory with a history of failure. But there is a shift there. Perhaps being criticized in places like Nature and Scientific American had an effect? One can hope!
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.
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.
Too long lifespan?
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.
Speaking as a researcher in this field, more people willing to volunteer for clinical trials is incredibly important.
Their underlying assumption is shown in, "Previous research has shown that the progression of Alzheimer’s disease is driven by a vicious cycle of the protein amyloid β (Aβ) inducing hyperactivity at the neuron level."
This is a widespread belief and has been the main target of attempted treatments for decades. Every one of which has failed. And therefore I predict that a drug trial based on this research will likewise fail.
So if that fails, what should we do instead?
See https://www.nature.com/articles/d41586-018-05719-4 for an overview of why it is reasonable that the root cause is infections and amyloid β is a symptom of our brains attempts to fight it off. Which explains why decades of drug trials aimed at disrupting the creation of amyloid β (which this does) have failed dismally.
As https://blogs.scientificamerican.com/observations/could-alzh... points out, treating people with the anti-herpes drug acyclovir was found to reduce the odds of getting Alzheimer's by 80%. Contrast this with the inability over many drug trials of any drugs aimed at amyloid β to demonstrate any effect on Alzheimer's at all.
As the old quote goes, "science progresses one funeral at a time". We're going to see ongoing research for a long time based on the idea that amyloid β is the cause of Alzheimer's. In the meantime if you have a family history of Alzheimer's, I would recommend getting a prescription for the only drug that has ever demonstrated any clinical success. Namely acyclovir. And start it before permanent damage has been done to your brain.
Or both. As I understand it, acyclovir is cleared from your system much more quickly than valacyclovir.
Anyway, I find (sample N=1) that acyclovir utterly fails to have any effect at all on my herpes outbreaks, but the other suppresses them. YMMV.
My Grandpa wasn't well with Alzheimers and vascular dementia for about a decade before he passed and whilst there was a lot of good in that time, there were some truly awful bits for everyone involved.
After he passed my Dad and I tried to avoid the conversation of "it runs in the family; this is going to happen to us" on a couple of occasions, and I don't know about yourself, but I've had that thought hanging over me ever since.
I was extremely lucky and the nursing home let me basically live there for the last week; I couldn't bare him being left alone. After a week of no sleep I found myself shuffling around the unit almost delirious at 4am and actually had a moment of "how do I know I'm the visitor and not the resident?" Would I actually know when it comes my turn - maybe it'd be better if I didn't.
I suppose it's almost analogous with "Did I ever come down after taking that drug?". I've broken plenty of bones and that really doesn't phase me, but the idea that I'd stop being able to reason my way through something terrifies me. I wish you absolutely all of the best.
Turned out it was a clotting problem. Genetic Factor 5 Leiden. I was having minor strokes a couple times a week. Each time would take about a month to recover mentally. But having them faster then that. Completely cleared up as soon as I went on blood thinners.
Later I learned whole extended family had been through this.
Dementia can have many causes, sometimes it’s something we know about, but hard to diagnosis.
The problem you also have with dementia/Alzheimer's is that it hard to be able to do euthanasia. I know some people are against this, but I am happy that my country offers this choice. I would probably go for it.