This is my field. There have been three major scandals in the "amyloid" field -- Sylvain Lesne, Eliezer Masliah, and lecanemab trials not informing patients they had the APOE4 variant, which is associated with cerebral amyloid angiopathy, a vascular condition that the same scientists who led those trials previously noted was correlated with cerebral hemorrhage side effects. Sylvain Lesne produced shitty research that was not that highly cited, below is my take on the field and my concerns regarding journalists poorly communicating the science in this story. My perspective on why we are behind other fields is in paragraph five. The next three paragraphs are just context as to why I think there is no singular “amyloid hypothesis,” and why this kind of journalism threatens our field despite a desperate need for dealing with fraud, too. I realize this is long, I am not a journalist, I am not a good communicator, I am a scientist. If anyone has advice, please share it with me, likewise with questions.
Not being clear about "amyloid" nomenclature threatens to throw the baby out with the bathwater, which will stall an Alzheimer's cure even more. Most proteins are "globular," think kind of round balls of scrunched up string, arranged in alpha-helices and some beta-sheets. "Amyloids" are spine-like fibrillar protein aggregates, where each vertebrate is a flattened version of a protein folded in beta-strands. The vertebrate is created by these beta-strands stacking into beta-sheets. Google "amyloid fiber" versus "globular protein" to see what I mean by this description.
"Amyloid BETA" is a usually disordered protein which can aggregate into ONE of the amyloid fibrils seen in Alzheimer's and other dementia patients' brains. Tau can form amyloid fibers, so can TDP-43, TMEM, alpha-synuclein, etc. This is a good link -- https://people.mbi.ucla.edu/sawaya/amyloidatlas/ -- if you want to see the cross-sections of all of the amyloid fiber structures the field has solved with useful annotations. One "amyloid hypothesis," for example, is that TAU hyperphosphorylation (the addition of a lot of very negatively charged post-translational modifications, think chemical ornaments you can add to a tree) leads to tau amyloid fibers, which then lead to amyloid-beta amyloid fibers. There is lots of speculation about the mechanism, whether amyloid fibers can also have enzymatic function that lead to metabolic dysregulation, whether certain amyloid fibers are actually functional and exist in everyone but that certain types or a certain amount is associated with disease, the catecholamine hypothesis is something that can’t be discounted, maybe amyloid fibers are just a downstream effect of a true ultimate cause (in which case, amyloid fibers are still an important clue, lots of people are doing experiments now where they see how they can get certain amyloid fibers in vitro using co-factors which may be one step back to the root cause).
Another "amyloid hypothesis" is that amyloid beta OLIGOMERs, some kind of non-fibrillar aggregate that we don't know the structure of but that we know contains proteins that usually also make amyloid fibers , causes Alzheimer's. This is what "amyloid beta *56" is, by the way, an oligomer, and what Lesne’s work argued. We find oligomers to be extremely hard to work with and I could write a paragraph or two about why, but the fact that this is true makes OLIGOMER research, some of which is probably legitimate, an easy target for fraud. When molecules are well-known to be extremely difficult to work with, if you try to replicate someone's experiments and you can't, it could be because the molecules are extremely difficult to work with or because the authors whose experiments you tried to replicate committed fraud. It’s easy to think “well, it must be me,” which is how people get away with it for so long.
So, why are we so far behind? Something important to note is that amyloid fiber structure on an atomic level has only recently been cracked. Consider that we've known the structure of DNA since the 50s, but we didn't know the structure of the MOST common amyloid fiber specific to Alzheimer's patients until 20 freaking 16 -- https://pubmed.ncbi.nlm.nih.gov/28678775/. The reason for this is that the method used to solve the structure of most proteins is x-ray crystallography, but nobody has ever successfully crystallized amyloid fibers except for very small fragments of them -- https://pubmed.ncbi.nlm.nih.gov/15944695/. People think this makes physical sense for reasons related to crystal symmetry. The 2016 structure was solved using cryo-EM, which is a relatively recent development and only won the Nobel in 2017. Prior, it was derided as “blobology” because you would get very coarse structures from cryo-EM -- https://pmc.ncbi.nlm.nih.gov/articles/PMC2726924/. So, the field had to wait for cryo-EM to improve, a big part of which was waiting for better computer vision algorithms (i.e. we use YOLO and various CNN-based algorithms, too, we had to wait for that shit just like Waymo), among other things.
Why is structure so important? Drugs have to physically interact with some kind of protein target. So, you should probably know the atomic model of the target so you can make use of computational modeling techniques that can help you figure out what binds to proteins. Alternatively, if you want to do a ton of biochemical screens, i.e. make a bunch of the target protein, treat it with various compounds, and see what sticks, you have to make sure you are correctly making the target protein. In other words, you don’t know you’ve successfully reproduced the target if you don’t know what the target is. And the exact fiber structure matters, since different structures appear to be correlated with different diseases. Then, you have to figure out a method to make that protein, which people also have done recently for various types. The alternative is waiting for brains from brain banks, which is very slow and doesn’t provide a lot of material. Keep in mind this also means you can’t verify your mouse models have the same structures, too.
I do not think these scandals significantly stalled an Alzheimer's cure. It's a genuinely tough field -- you can't do brain biopsies, amyloids are a tricky protein to work with, we didn’t know the structure until 9 years ago. I think there are a lot of people who feel like they were locked out of funding opportunities because of the focus on amyloid-beta. Maybe this is true, I don’t know. The lab I’m in has worked on tau for decades.
Another point -- neurodegeneration starts far before symptoms show up. A lot of the recent drugs were designed for what is basically metastatic cancer. Learning more about earlier stages of neurodegeneration, which we can do with PET-ligands designed to bind to fibers, the recent p-tau blood test, etc. is necessary to uh... treat stage 1 or 2 cancer equivalent.
Finally, I have to get political here, considering recent events. I’m not a professional communicator. Most scientists aren’t. It is things like this that are the reason we are being threatened with funding cuts. Who will read nine paragraphs that I think are necessary context for all of this? But it is much easier to read an article like this, where the same point is repeated multiple times, with some “they said this,” “they said that,” etc. than to understand even a small portion of a field. More people will do the former, and then apparently call for executions without any way to judge who will be executed. And I sit down to write code for my experiments, click on one link, and see what I perceive as harmful information, and there goes apparently half an hour. I can either let this kind of stuff lead to my funding being cut, or reply to it and slow down my research.
I know a lot of legitimate research supports various versions of the amyloid hypothesis, but I don't buy that these likely fraudsters had minimal impact.
You said that Lesné was "not that highly cited". But his main fraudulent paper was cited 2,300 times, making it the fifth most highly cited Alzheimer's paper since 2006! [1]
Berislav Zlokovic's likely fraudulent papers were cited 11,500 times! [2]
It's hard to imagine these highly papers didn't redirect at least some scientists to do pointless followup studies. Of course, in the counterfactual world the scientists might still have been doing pointless studies, but we'll never know...
I disagree with you that you are not a good communicator. While I am generally science literate, I know roughly nothing about this field. I found your comment clear and relatively easy to read, if a little dense with field-specific terminology.
I think you conveyed the necessary context well. Thanks for taking the time to do so.
Thank you so much for this! Would brain biopsies (if they could be performed safely, widely) be more beneficial than the multimodal/multi-omic datasets now emerging that combine PET/CSF/Blood? Also, how much information would PET-ligands designed to bind to fibres and the p-tau blood test yield towards designing interventions? What exactly would they reveal that we don't know already?
Thanks for your response. One confusing thing as an outsider is that amyloid aggregates seems like fraud, but tau aggregates still seems to be a promising line of research.
I read these paragraphs. I’m incredibly grateful for the context and glad people are working on this. Scientists aren’t perfect but science is all we’ve got when it comes to this shithead if a disease.
> But it is much easier to read an article like this, where the same point is repeated multiple times, with some “they said this,” “they said that,” etc. than to understand even a small portion of a field. More people will do the former, and then apparently call for executions without any way to judge who will be executed. And I sit down to write code for my experiments, click on one link, and see what I perceive as harmful information, and there goes apparently half an hour. I can either let this kind of stuff lead to my funding being cut, or reply to it and slow down my research
Am I unreasonable to think that funding ought to be re-directed elsewhere, given that we 1) already have effective anti-amyloid monoclonal antibodies, and 2) they don't seem to work that well, and 3) there are alternatives, like the chronic inflammation hypothesis, that have supporting evidence? (e.g., https://www.nature.com/articles/s41591-024-03201-5)
There are many reasons anti-amyloid mABs might not work that well besides "amyloid hypothesis is bunk." You are giving them to very late-stage patients, they don't actually work that well if you look at the data, and some people also think that if you disaggregate fibers without a molecule that also inhibits new aggregation, you are just creating more "seeds" that can grow into more amyloids. I think the fact that they do SOMETHING despite all these unanswered questions and also their terrible side effects actually suggests we might be on the right track.
> 1) already have effective anti-amyloid monoclonal antibodies, and 2) they don't seem to work that well
I fear you may be falling into the exact trap that the person you replied to, is warning against.
There is not just one thing called "amyloid", so not only are the "anti-amyloid monoclonal antibodies" not effective against all amyloid, the amyloid against which they are effective may well not be disease-contributing amyloid.
The state of the field is much more complicated that deciding between pop-sci summaries of "amyloid bad" and "amyloid irrelevant" and directing funding accordingly.
Yeah, this reminds me of "asbestos" which is not a single thing and has many non-dangerous examples, but has been banned because a few of them (and contamination is a worry) are a significant hazard. If the different structures were just called something different, they might have significant commercial applications, but "asbestos".
Same thing with MRI with the removal of Nuclear from NMR. Sure the 3D imaging is cool, but you know that they had to remove that N from the name for marketing.
Ok, and then there's EUV lithography. Don't call it X-Ray lithography even though it's 13nm, because there were decades of expensive failures with that marketing.
To step back for a second, why is the question always re-directing funding when science funding overall has been steadily eroded by inflation and cuts since the 60s? A few months ago, I looked up the percentage of the American population that has PhDs and how it has changed over time. We have so, so, so much more advanced work and technical needs now that would benefit from them.
To answer your question more specifically, our lab is actively trying to collaborate with people working on questions related to chronic inflammation (I am not sure what the funding status is, but I know someone from our lab is working there). In particular, microglial activation. Not to get lazy with cancer analogies, but if you look at what causes even a single cancer, it's often hundreds of events lining up perfectly. The question is, which one do we target to make an effective drug? The honest answer I have to this is that it's wishful thinking to think that that decision should be made at the level of basic science. How the funding and research ecosystem is supposed to work, is academia is supposed to explore all kinds of avenues, and then industry is supposed to exploit them and push the most promising avenues after. The problem is that when there's a crunch on science funding, "this is an unexplored avenue" is not enough, and you basically begin to take on the role of industry without any of the money. I think fraud is heavily incentivized by the funding crunch, too, actually. In the case of Eliezer Masalah, my impression is that his fraud was photoshopping images and faking experiments to add to collaborators' points to support other experiments that WERE actually conducted and made the points. I assume he was trying to get a very high impact factor for funding and promotions, but was trying to minimize the chances that he would get caught by making sure his research was part of works he assumed would be reproducible given that he assumed the others' research was legitimate. I haven't kept up with the case since it initially broke, though, and I didn't go through it as closely as I should have (I also do not focus much on alpha-synuclein).
But, if you really want an answer as to why I think there is more funding on amyloids than chronic inflammation, it is that amyloids are Rome. Imagine a funnel. Chronic inflammation is near the entry to it, along with many other things. But shingles is not the only thing that might cause chronic inflammation that might cause Alzheimer's. Herpes has also been linked. So basically everything is at the very top of the funnel. But the reason people study amyloids is that they are at the very bottom of it. Chronic inflammation seems to cause them to misfold, but so do certain mutations, so if we can develop a drug that disaggregates and/or inhibits the growth of amyloids, we are stopping more causes than just looking at chronic inflammation, which is one of many.
> Who will read nine paragraphs that I think are necessary context for all of this?
They are very interesting, but I'd have to be convinced that they were necessary context. Because the question that I think is important is whether this was true and widespread:
> I think there are a lot of people who feel like they were locked out of funding opportunities because of the focus on amyloid-beta. Maybe this is true, I don’t know.
And you don't know. I don't know either.
We can't say that anything would be farther along if these frauds had not happened, because that is a counterfactual. We can just guess that if we spend resources in areas that didn't have as much fraud surrounding them, we would be more likely to be farther along. Any argument otherwise is an argument that the direction and funding of research doesn't ever really matter.
I don't think any avenue of research should be abandoned if anybody still sees any possible value in it. But I know that funding decisions heavily influenced by fraudulent research are not going to be better made than decisions not influenced by fraud; and that if we were making decisions based on fraud over a long period of time, it is safe to assume that there was a loss. If we want to be less likely to repeat this loss, we probably need to change how we evaluate where to allocate funding.
Thank you for your comment. I am not saying the field was not stalled because of these frauds, I am saying I do not think it was significantly stalled. I think fraud is an easy scapegoat for broader issues, especially when the case that people keep referring to is whether a single amyloid beta oligomer species is involved. There are some very esteemed researchers who do not believe oligomers are physiologically relevant or discrete enough to be analyzed at all. I am trying to point out the ways that "amyloid hypothesis" actually refers to many distinct things to try to prevent very non-specific reactions like another comment that replied to me had, where we decide to throw out amyloid research entirely for chronic inflammation, etc.
If we want less fraud, we need less incentives for fraud. What do you think the easiest route to take is when funding in a field that already attracts some nutso people is cut every year? That so little fraud happens is a testament to the integrity of most scientists. I grew up part of an ascetic religious sect. The personality types of many scientists in the field are that of the hermits I knew as a child. You probably cannot totally get rid of fraud, some people cannot really seem to produce anything themselves, they exist, they will find some way to survive (often better than those who are not this way). You can keep rates of fraud low, but if you think it is more prevalent than it is, you risk developing a social autoimmune disease. Remember that means-testing has its own costs, too.
> I think there are a lot of people who feel like they were locked out of funding opportunities because of the focus on amyloid-beta. Maybe this is true, I don’t know.
...
You completely excluded the last sentence of the quote by the GP. That sentence at least partially addresses your concern:
> The lab I’m in has worked on tau for decades.
The lab the GP is working in has been, for decades, funded and working to study ameloid tau -- one of the very alternative hypotheses that are under study. Most of the entire post was about all the other hypotheses that are active and regularly funded.
No one is omniscient, no one can know exactly the right set of funding to get the optimal scientific outcome with the least amount of money. That omniscience isn't going to happen no matter how awesome AI is.
The best course for medical breakthroughs is to fund multiple hypotheses at once which is exactly what NIH does. The more funding to allow research into various hypotheses the better. Whatever it is doge is doing straight shutting shit down is the incompetent fools course plotted by megalomaniacal and ignorant billionaires.
as someone who is not in this field (purely doing CS research): haven't recent advances in ML "solved" most protein structures and made x-ray crystallography obsolete?
Scientists like Sylvain Lesné whose alleged misconduct cost us over a decade investigating a dead end hypothesis should face substantial prison time. Considerable people have faced the horror of this disease with no hope for a cure in sight because charlatans like this likely manipulated data in the name of making their own careers.
There is an incredibly valuable and interesting comment ranked below yours that gives enormous amounts of context on the Amyloid hypothesis and the state of the field. I don’t have the power to make that the top-ranked comment and all the “we need to punish” comments lower ranked. But I do wish the posters and other readers on HN would help to make that happen.
I read the comment you refer to, and it does have a lot of useful context. That said (and here I'm quoting a reply to that comment), the commenter claims that Lesné was "not that highly cited", though his main fraudulent paper was cited 2,300 times, making it the fifth most highly cited Alzheimer's paper since 2006. That seems bogus on its face.
Separately, I think it's legitimate for calls for scientific fraudsters to go to jail to rise to the top. There's no contradiction between wanting this, and wanting a more nuanced understanding of the field.
My mother has Alzheimer's, so this matters a lot to me, both for her and myself and my kids in the future.
It has never felt reasonable to me that a small number of papers (highly cited or not) from 2006 could somehow be responsible for our failure to cure this disease over the past decades. It seems so emotionally tempting to give people a scapegoat that it frankly rings all my "too good to be true" alarm bells. And bluntly, it's just implausible.
Like it or not: if we're going to get a cure for this horrible disease, it's going to come out of the scientific community. My fear is that a bunch of non-experts are going to barge in with a weakly-understood idea about what is happening in the field, demand "reforms" with implications they don't understand, and in the process doom millions of people to agony and suffering.
In my mind this very much depends on who was tricked here. If the research was funded by companies, then arguably they should just have better oversight and the loss of their investment is already "punishment" to incentivice that better oversight. If it was public money, then it depends more on the nature of the fraud. I could concieve of a circumstance where I would also argue for a lapse in oversight and therefore a sort of "diffusion" of the responsibility.
I don't think it's certain that anything illegal happened here. It was certainly wrong, but wrong how?
>If the research was funded by companies, then arguably they should just have better oversight and the loss of their investment is already "punishment" to incentivice that better oversight.
This is not at all how the law works. You can't fool investors on purpose then shrug it off as "I win, they should have done their due diligence and second-guessed every aspect of my work that I intentionally falsified" lol. What you're arguing for is equivalent to a diffusion of responsibility for accounting fraud, as if the victims deserve it because auditors didn't detect it immediately.
I don't know the whole story but deceptive practices (deliberate wrongdoing) need to be punished, if that is what happened here.
That is explicitly illegal in the stock market, and companies are frequently sued over deceptive practices. They have whole PR departments dedicated to making sure that they convey accurate (or at least defensible) information to investors.
Enforcement is a different matter entirely. I was originally responding to an argument about the legality of deception. A lack of enforcement does not make it more defensible.
No doubt! My father is suffering from Alzheimer’s and I have just been told that I have a few months left due to colorectal cancer. I can only wonder if there are/was/is something delaying better treatments for my condition. I am now on the hunt for alternative treatment options for me, and one of the molecules that has been suggested is highly controversial as it was suggested as a covid treatment.
I hope that you can find an alternative treatment that works for you and that however many days you left, few or many, are filled with joy, love, and comfort. My sister just finished her recovery for breast cancer and her journey opened my eyes to the classic 'life is short.'
They have potentially condemned hundreds of thousands of people to suffer with this disease unnecessarily. The level of harm they have caused may be far worse than anything Josef Mengele did.
I work in neurotech/sleeptech and work with Alzheimer's researchers.
This is sensationalist and one-sided.
Alzheimer's is the most common form of dementia, and it is not clearly understood. It is potentially the most common form because it is not understood and there are many, myself among them, who believe that multiple different diseases are being assigned a single title because we don't understand the disease enough.
This isn't to say the Amyloid hypothesis is correct, it may be correct in a number of cases, but the Type 3 Diabetes may also be correct.
The Amyloid Hypothesis has not been disproven. Yes, misrepresented data in a few studies have significantly put into question the reliability, however hundreds of other not "doctored" studies have shown the hypothesis holds significant promise.
The pharmaceutical companies did not make up the format of the disease in order to sell drugs, and the current drugs are not very effective, but that doesn't mean the theory is wrong. Just because amyloid build up is a marker of the disease does not mean that removing this metabolic waste would reverse the disease. That's like saying blowing your nose would cure the common cold.
In the case of AD, the suspicion is that the Amyloid/Tau build up damages the neurons ability to signal within the brain, like a blockage in a pipe that causes the pipe to break. Removing the blockage does not repair the pipe.
So why bother removing it at all?
A researcher we work with has posited a theory (which is fairly new, but I'm not sure she is the first) that amyloid build up reduces the power of delta slow waves, and the related glymphatic flushing of metabolic waste. This is why the drugs might be valuable (I'll say might be, rather than are), increasing the removal of waste slows further progression of the disease.
Having said that, there is a point in time where slowing progression is just lengthening time in poor health, and is not valuable, but prior to that, it can be valuable (I'll leave it up to individuals to decide what is right for them or their family members).
We've been developing slow-wave enhancement technology at Affectable Sleep [1] for the last 5 years, and similar tech has shown early promise in people with AD [2] as well as potential preventative in elderly people [3].
What do doctors prescribe nowadays? Same discredited meds?
How about SSRIs, for which much of the research does not provide supporting evidence? E.g. there's a 2022 meta-study by Moncrieff et al that shows there's no consistent evidence tying serotonin to depression. An earlier 2008 placebo-controlled study by Kirsch et al shows that SSRIs are barely any better than placebo.
IOW, SSRIs are useless horseshit for the vast majority of people (especially in the absence of e.g. CBT) and the theory behind them is not supported by evidence. Why are they still prescribed?
It is now well known that serotonin uptake cannot explain the effect of SSRIs and that we don't actually know how they work- but that doesn't mean they don't work. Most drugs have many effects (we call some of them side effects) and this isn't the first drug where we thought we knew how it worked and ended up being wrong.
Some have found flaws with Kirsh's study and there is still an ongoing debate about effectiveness. [1] I am not a fan of prescribing so many people a drug that we don't know how it even works for what is often just a small improvement, but I don't think its accurate to say they are useless.
I suspect SSRIs would work a lot better if we could select a better cohort for them. My sister comment notes how depression can be a symptom of a more treatable/precise disorder and so Depression becomes a broad church of several disorders when they present mildly or are not diagnosed for some other reason.
I think I read that amyloid may be a body immune reaction to infection which is why targeting that rather than the infection is ineffective. (not expert on this but the article is interesting).
I suspect SSRIs are prescribed because they are easy to prescribe.
I think they don't work because Depression, like Alzheimer's, is poorly defined.
From a population genetics perspective we can find clear genetic signals for other psychiatric disorders such as Schizophrenia, ADHD, etc. But Depression is notoriously difficult to identify any genetic signal for. Its my opinion that this is because Depression is more often a symptom of another psychiatric disorder and only rarely is the root cause just Depression itself.
Many folks with ADHD, Bipolar, or other "mild" disorders go undiagnosed and get the Depression label instead and this muddies the waters.
To be fair, there's plenty to lambaste him for. But that's not the question. The question is, what's to prevent my doctor from prescribing "treatments" that are based on recently (or not so recently) discredited research?
The main thing that RFK worries people about are vaccinations and his anti-vax and anti-FDA stance, that's it. Saying that people are against "healthy eating and meditating" is somewhere between an obviously stupid lie and a misrepresentation you should be ashamed of.
No, but the careers and reputation of those who lead this avenue and undermined good science must be conclusively ruined.
We can start by letting the truth come light in stark and unambiguous terms again and again, along with the billions of dollars in damage and hundreds of thousands if not millions of families left to suffer thanks to prestige and fraud.
Better yet, also reward the risk takers then and now; trying to chase good science as hazardous as it was.
I know this is a flippant comment, but do you really think this would solve the problem? I feel like this would just lead to academic misconduct never being reported. It is hard enough to get someone to report a fellow academic for fraud when the only consequence is professional reputation; do you really think ANYONE would turn in a colleague when the consequence is death?
Plus, people would be so scared that they will make a mistake that will be interpreted as fraud that no one will want to publish research.
This is my field. There have been three major scandals in the "amyloid" field -- Sylvain Lesne, Eliezer Masliah, and lecanemab trials not informing patients they had the APOE4 variant, which is associated with cerebral amyloid angiopathy, a vascular condition that the same scientists who led those trials previously noted was correlated with cerebral hemorrhage side effects. Sylvain Lesne produced shitty research that was not that highly cited, below is my take on the field and my concerns regarding journalists poorly communicating the science in this story. My perspective on why we are behind other fields is in paragraph five. The next three paragraphs are just context as to why I think there is no singular “amyloid hypothesis,” and why this kind of journalism threatens our field despite a desperate need for dealing with fraud, too. I realize this is long, I am not a journalist, I am not a good communicator, I am a scientist. If anyone has advice, please share it with me, likewise with questions.
Not being clear about "amyloid" nomenclature threatens to throw the baby out with the bathwater, which will stall an Alzheimer's cure even more. Most proteins are "globular," think kind of round balls of scrunched up string, arranged in alpha-helices and some beta-sheets. "Amyloids" are spine-like fibrillar protein aggregates, where each vertebrate is a flattened version of a protein folded in beta-strands. The vertebrate is created by these beta-strands stacking into beta-sheets. Google "amyloid fiber" versus "globular protein" to see what I mean by this description.
"Amyloid BETA" is a usually disordered protein which can aggregate into ONE of the amyloid fibrils seen in Alzheimer's and other dementia patients' brains. Tau can form amyloid fibers, so can TDP-43, TMEM, alpha-synuclein, etc. This is a good link -- https://people.mbi.ucla.edu/sawaya/amyloidatlas/ -- if you want to see the cross-sections of all of the amyloid fiber structures the field has solved with useful annotations. One "amyloid hypothesis," for example, is that TAU hyperphosphorylation (the addition of a lot of very negatively charged post-translational modifications, think chemical ornaments you can add to a tree) leads to tau amyloid fibers, which then lead to amyloid-beta amyloid fibers. There is lots of speculation about the mechanism, whether amyloid fibers can also have enzymatic function that lead to metabolic dysregulation, whether certain amyloid fibers are actually functional and exist in everyone but that certain types or a certain amount is associated with disease, the catecholamine hypothesis is something that can’t be discounted, maybe amyloid fibers are just a downstream effect of a true ultimate cause (in which case, amyloid fibers are still an important clue, lots of people are doing experiments now where they see how they can get certain amyloid fibers in vitro using co-factors which may be one step back to the root cause).
Another "amyloid hypothesis" is that amyloid beta OLIGOMERs, some kind of non-fibrillar aggregate that we don't know the structure of but that we know contains proteins that usually also make amyloid fibers , causes Alzheimer's. This is what "amyloid beta *56" is, by the way, an oligomer, and what Lesne’s work argued. We find oligomers to be extremely hard to work with and I could write a paragraph or two about why, but the fact that this is true makes OLIGOMER research, some of which is probably legitimate, an easy target for fraud. When molecules are well-known to be extremely difficult to work with, if you try to replicate someone's experiments and you can't, it could be because the molecules are extremely difficult to work with or because the authors whose experiments you tried to replicate committed fraud. It’s easy to think “well, it must be me,” which is how people get away with it for so long.
So, why are we so far behind? Something important to note is that amyloid fiber structure on an atomic level has only recently been cracked. Consider that we've known the structure of DNA since the 50s, but we didn't know the structure of the MOST common amyloid fiber specific to Alzheimer's patients until 20 freaking 16 -- https://pubmed.ncbi.nlm.nih.gov/28678775/. The reason for this is that the method used to solve the structure of most proteins is x-ray crystallography, but nobody has ever successfully crystallized amyloid fibers except for very small fragments of them -- https://pubmed.ncbi.nlm.nih.gov/15944695/. People think this makes physical sense for reasons related to crystal symmetry. The 2016 structure was solved using cryo-EM, which is a relatively recent development and only won the Nobel in 2017. Prior, it was derided as “blobology” because you would get very coarse structures from cryo-EM -- https://pmc.ncbi.nlm.nih.gov/articles/PMC2726924/. So, the field had to wait for cryo-EM to improve, a big part of which was waiting for better computer vision algorithms (i.e. we use YOLO and various CNN-based algorithms, too, we had to wait for that shit just like Waymo), among other things.
Why is structure so important? Drugs have to physically interact with some kind of protein target. So, you should probably know the atomic model of the target so you can make use of computational modeling techniques that can help you figure out what binds to proteins. Alternatively, if you want to do a ton of biochemical screens, i.e. make a bunch of the target protein, treat it with various compounds, and see what sticks, you have to make sure you are correctly making the target protein. In other words, you don’t know you’ve successfully reproduced the target if you don’t know what the target is. And the exact fiber structure matters, since different structures appear to be correlated with different diseases. Then, you have to figure out a method to make that protein, which people also have done recently for various types. The alternative is waiting for brains from brain banks, which is very slow and doesn’t provide a lot of material. Keep in mind this also means you can’t verify your mouse models have the same structures, too.
I do not think these scandals significantly stalled an Alzheimer's cure. It's a genuinely tough field -- you can't do brain biopsies, amyloids are a tricky protein to work with, we didn’t know the structure until 9 years ago. I think there are a lot of people who feel like they were locked out of funding opportunities because of the focus on amyloid-beta. Maybe this is true, I don’t know. The lab I’m in has worked on tau for decades.
Another point -- neurodegeneration starts far before symptoms show up. A lot of the recent drugs were designed for what is basically metastatic cancer. Learning more about earlier stages of neurodegeneration, which we can do with PET-ligands designed to bind to fibers, the recent p-tau blood test, etc. is necessary to uh... treat stage 1 or 2 cancer equivalent.
Finally, I have to get political here, considering recent events. I’m not a professional communicator. Most scientists aren’t. It is things like this that are the reason we are being threatened with funding cuts. Who will read nine paragraphs that I think are necessary context for all of this? But it is much easier to read an article like this, where the same point is repeated multiple times, with some “they said this,” “they said that,” etc. than to understand even a small portion of a field. More people will do the former, and then apparently call for executions without any way to judge who will be executed. And I sit down to write code for my experiments, click on one link, and see what I perceive as harmful information, and there goes apparently half an hour. I can either let this kind of stuff lead to my funding being cut, or reply to it and slow down my research.
I know a lot of legitimate research supports various versions of the amyloid hypothesis, but I don't buy that these likely fraudsters had minimal impact.
You said that Lesné was "not that highly cited". But his main fraudulent paper was cited 2,300 times, making it the fifth most highly cited Alzheimer's paper since 2006! [1]
Berislav Zlokovic's likely fraudulent papers were cited 11,500 times! [2]
It's hard to imagine these highly papers didn't redirect at least some scientists to do pointless followup studies. Of course, in the counterfactual world the scientists might still have been doing pointless studies, but we'll never know...
[1] https://www.science.org/content/article/potential-fabricatio... [2] https://www.science.org/content/article/misconduct-concerns-...
I disagree with you that you are not a good communicator. While I am generally science literate, I know roughly nothing about this field. I found your comment clear and relatively easy to read, if a little dense with field-specific terminology.
I think you conveyed the necessary context well. Thanks for taking the time to do so.
> I can either let this kind of stuff lead to my funding being cut, or reply to it and slow down my research.
Research is always going to require some of your time spent justifying the funding.
Would you be up to chat sometime? Would love to fund a research startup to work on some of this more — matt@scifounders.com
Thank you so much for this! Would brain biopsies (if they could be performed safely, widely) be more beneficial than the multimodal/multi-omic datasets now emerging that combine PET/CSF/Blood? Also, how much information would PET-ligands designed to bind to fibres and the p-tau blood test yield towards designing interventions? What exactly would they reveal that we don't know already?
Thanks for your response. One confusing thing as an outsider is that amyloid aggregates seems like fraud, but tau aggregates still seems to be a promising line of research.
Both to an outsider look like protein aggregates.
science shouldn't have to be done with the fear of not being read fully, the system needs to be improved so you all can go deep
thanks for the long comment
I read these paragraphs. I’m incredibly grateful for the context and glad people are working on this. Scientists aren’t perfect but science is all we’ve got when it comes to this shithead if a disease.
> But it is much easier to read an article like this, where the same point is repeated multiple times, with some “they said this,” “they said that,” etc. than to understand even a small portion of a field. More people will do the former, and then apparently call for executions without any way to judge who will be executed. And I sit down to write code for my experiments, click on one link, and see what I perceive as harmful information, and there goes apparently half an hour. I can either let this kind of stuff lead to my funding being cut, or reply to it and slow down my research
Am I unreasonable to think that funding ought to be re-directed elsewhere, given that we 1) already have effective anti-amyloid monoclonal antibodies, and 2) they don't seem to work that well, and 3) there are alternatives, like the chronic inflammation hypothesis, that have supporting evidence? (e.g., https://www.nature.com/articles/s41591-024-03201-5)
There are many reasons anti-amyloid mABs might not work that well besides "amyloid hypothesis is bunk." You are giving them to very late-stage patients, they don't actually work that well if you look at the data, and some people also think that if you disaggregate fibers without a molecule that also inhibits new aggregation, you are just creating more "seeds" that can grow into more amyloids. I think the fact that they do SOMETHING despite all these unanswered questions and also their terrible side effects actually suggests we might be on the right track.
> 1) already have effective anti-amyloid monoclonal antibodies, and 2) they don't seem to work that well
I fear you may be falling into the exact trap that the person you replied to, is warning against.
There is not just one thing called "amyloid", so not only are the "anti-amyloid monoclonal antibodies" not effective against all amyloid, the amyloid against which they are effective may well not be disease-contributing amyloid.
The state of the field is much more complicated that deciding between pop-sci summaries of "amyloid bad" and "amyloid irrelevant" and directing funding accordingly.
Yeah, this reminds me of "asbestos" which is not a single thing and has many non-dangerous examples, but has been banned because a few of them (and contamination is a worry) are a significant hazard. If the different structures were just called something different, they might have significant commercial applications, but "asbestos".
Same thing with MRI with the removal of Nuclear from NMR. Sure the 3D imaging is cool, but you know that they had to remove that N from the name for marketing.
Ok, and then there's EUV lithography. Don't call it X-Ray lithography even though it's 13nm, because there were decades of expensive failures with that marketing.
To step back for a second, why is the question always re-directing funding when science funding overall has been steadily eroded by inflation and cuts since the 60s? A few months ago, I looked up the percentage of the American population that has PhDs and how it has changed over time. We have so, so, so much more advanced work and technical needs now that would benefit from them.
To answer your question more specifically, our lab is actively trying to collaborate with people working on questions related to chronic inflammation (I am not sure what the funding status is, but I know someone from our lab is working there). In particular, microglial activation. Not to get lazy with cancer analogies, but if you look at what causes even a single cancer, it's often hundreds of events lining up perfectly. The question is, which one do we target to make an effective drug? The honest answer I have to this is that it's wishful thinking to think that that decision should be made at the level of basic science. How the funding and research ecosystem is supposed to work, is academia is supposed to explore all kinds of avenues, and then industry is supposed to exploit them and push the most promising avenues after. The problem is that when there's a crunch on science funding, "this is an unexplored avenue" is not enough, and you basically begin to take on the role of industry without any of the money. I think fraud is heavily incentivized by the funding crunch, too, actually. In the case of Eliezer Masalah, my impression is that his fraud was photoshopping images and faking experiments to add to collaborators' points to support other experiments that WERE actually conducted and made the points. I assume he was trying to get a very high impact factor for funding and promotions, but was trying to minimize the chances that he would get caught by making sure his research was part of works he assumed would be reproducible given that he assumed the others' research was legitimate. I haven't kept up with the case since it initially broke, though, and I didn't go through it as closely as I should have (I also do not focus much on alpha-synuclein).
But, if you really want an answer as to why I think there is more funding on amyloids than chronic inflammation, it is that amyloids are Rome. Imagine a funnel. Chronic inflammation is near the entry to it, along with many other things. But shingles is not the only thing that might cause chronic inflammation that might cause Alzheimer's. Herpes has also been linked. So basically everything is at the very top of the funnel. But the reason people study amyloids is that they are at the very bottom of it. Chronic inflammation seems to cause them to misfold, but so do certain mutations, so if we can develop a drug that disaggregates and/or inhibits the growth of amyloids, we are stopping more causes than just looking at chronic inflammation, which is one of many.
Thanks for your thoughtful replies
> Who will read nine paragraphs that I think are necessary context for all of this?
They are very interesting, but I'd have to be convinced that they were necessary context. Because the question that I think is important is whether this was true and widespread:
> I think there are a lot of people who feel like they were locked out of funding opportunities because of the focus on amyloid-beta. Maybe this is true, I don’t know.
And you don't know. I don't know either.
We can't say that anything would be farther along if these frauds had not happened, because that is a counterfactual. We can just guess that if we spend resources in areas that didn't have as much fraud surrounding them, we would be more likely to be farther along. Any argument otherwise is an argument that the direction and funding of research doesn't ever really matter.
I don't think any avenue of research should be abandoned if anybody still sees any possible value in it. But I know that funding decisions heavily influenced by fraudulent research are not going to be better made than decisions not influenced by fraud; and that if we were making decisions based on fraud over a long period of time, it is safe to assume that there was a loss. If we want to be less likely to repeat this loss, we probably need to change how we evaluate where to allocate funding.
Thank you for your comment. I am not saying the field was not stalled because of these frauds, I am saying I do not think it was significantly stalled. I think fraud is an easy scapegoat for broader issues, especially when the case that people keep referring to is whether a single amyloid beta oligomer species is involved. There are some very esteemed researchers who do not believe oligomers are physiologically relevant or discrete enough to be analyzed at all. I am trying to point out the ways that "amyloid hypothesis" actually refers to many distinct things to try to prevent very non-specific reactions like another comment that replied to me had, where we decide to throw out amyloid research entirely for chronic inflammation, etc.
If we want less fraud, we need less incentives for fraud. What do you think the easiest route to take is when funding in a field that already attracts some nutso people is cut every year? That so little fraud happens is a testament to the integrity of most scientists. I grew up part of an ascetic religious sect. The personality types of many scientists in the field are that of the hermits I knew as a child. You probably cannot totally get rid of fraud, some people cannot really seem to produce anything themselves, they exist, they will find some way to survive (often better than those who are not this way). You can keep rates of fraud low, but if you think it is more prevalent than it is, you risk developing a social autoimmune disease. Remember that means-testing has its own costs, too.
> I think there are a lot of people who feel like they were locked out of funding opportunities because of the focus on amyloid-beta. Maybe this is true, I don’t know.
...
You completely excluded the last sentence of the quote by the GP. That sentence at least partially addresses your concern:
> The lab I’m in has worked on tau for decades.
The lab the GP is working in has been, for decades, funded and working to study ameloid tau -- one of the very alternative hypotheses that are under study. Most of the entire post was about all the other hypotheses that are active and regularly funded.
No one is omniscient, no one can know exactly the right set of funding to get the optimal scientific outcome with the least amount of money. That omniscience isn't going to happen no matter how awesome AI is.
The best course for medical breakthroughs is to fund multiple hypotheses at once which is exactly what NIH does. The more funding to allow research into various hypotheses the better. Whatever it is doge is doing straight shutting shit down is the incompetent fools course plotted by megalomaniacal and ignorant billionaires.
as someone who is not in this field (purely doing CS research): haven't recent advances in ML "solved" most protein structures and made x-ray crystallography obsolete?
Very much no.
https://www.nature.com/articles/s41592-023-02087-4
Thats a handy article. Anyone in the field knows the title of this is implicitly true but its not at all obvious to the lay reader.
Scientists like Sylvain Lesné whose alleged misconduct cost us over a decade investigating a dead end hypothesis should face substantial prison time. Considerable people have faced the horror of this disease with no hope for a cure in sight because charlatans like this likely manipulated data in the name of making their own careers.
There is an incredibly valuable and interesting comment ranked below yours that gives enormous amounts of context on the Amyloid hypothesis and the state of the field. I don’t have the power to make that the top-ranked comment and all the “we need to punish” comments lower ranked. But I do wish the posters and other readers on HN would help to make that happen.
thank you for mentioning this comment, it was very in depth and I agree I think it should be ranked higher
I read the comment you refer to, and it does have a lot of useful context. That said (and here I'm quoting a reply to that comment), the commenter claims that Lesné was "not that highly cited", though his main fraudulent paper was cited 2,300 times, making it the fifth most highly cited Alzheimer's paper since 2006. That seems bogus on its face.
Separately, I think it's legitimate for calls for scientific fraudsters to go to jail to rise to the top. There's no contradiction between wanting this, and wanting a more nuanced understanding of the field.
My mother has Alzheimer's, so this matters a lot to me, both for her and myself and my kids in the future.
It has never felt reasonable to me that a small number of papers (highly cited or not) from 2006 could somehow be responsible for our failure to cure this disease over the past decades. It seems so emotionally tempting to give people a scapegoat that it frankly rings all my "too good to be true" alarm bells. And bluntly, it's just implausible.
Like it or not: if we're going to get a cure for this horrible disease, it's going to come out of the scientific community. My fear is that a bunch of non-experts are going to barge in with a weakly-understood idea about what is happening in the field, demand "reforms" with implications they don't understand, and in the process doom millions of people to agony and suffering.
There should be some laws that were broken. Fraud in order to obtain research grants, fraud in order to maintain labs, etc etc.
In my mind this very much depends on who was tricked here. If the research was funded by companies, then arguably they should just have better oversight and the loss of their investment is already "punishment" to incentivice that better oversight. If it was public money, then it depends more on the nature of the fraud. I could concieve of a circumstance where I would also argue for a lapse in oversight and therefore a sort of "diffusion" of the responsibility.
I don't think it's certain that anything illegal happened here. It was certainly wrong, but wrong how?
>If the research was funded by companies, then arguably they should just have better oversight and the loss of their investment is already "punishment" to incentivice that better oversight.
This is not at all how the law works. You can't fool investors on purpose then shrug it off as "I win, they should have done their due diligence and second-guessed every aspect of my work that I intentionally falsified" lol. What you're arguing for is equivalent to a diffusion of responsibility for accounting fraud, as if the victims deserve it because auditors didn't detect it immediately.
I don't know the whole story but deceptive practices (deliberate wrongdoing) need to be punished, if that is what happened here.
That happens all the time in the stock market and rarely anyone gets punished.
That is explicitly illegal in the stock market, and companies are frequently sued over deceptive practices. They have whole PR departments dedicated to making sure that they convey accurate (or at least defensible) information to investors.
I know it’s illegal but it’s still happening in various ways. Yes, once in a while investors do sue and win
Enforcement is a different matter entirely. I was originally responding to an argument about the legality of deception. A lack of enforcement does not make it more defensible.
No doubt! My father is suffering from Alzheimer’s and I have just been told that I have a few months left due to colorectal cancer. I can only wonder if there are/was/is something delaying better treatments for my condition. I am now on the hunt for alternative treatment options for me, and one of the molecules that has been suggested is highly controversial as it was suggested as a covid treatment.
The history of science is full of false starts ...
Ivermectin may or may not be effective against various cancers .. but it is a very safe molecule.
Look at the research independent of popular and institutional opinion.
If you can be part of a well run trial - of any kind, for any treatment - you give us all something of great value.
I can only hope things go well for you, and thank you for your courage.
I hope that you can find an alternative treatment that works for you and that however many days you left, few or many, are filled with joy, love, and comfort. My sister just finished her recovery for breast cancer and her journey opened my eyes to the classic 'life is short.'
Anti-body drug conjugates are a new promising technique in the treatment of cancer. Lots of these in the queue
https://www.bbc.com/storyworks/rewriting-cancer/the-exciting...
They have potentially condemned hundreds of thousands of people to suffer with this disease unnecessarily. The level of harm they have caused may be far worse than anything Josef Mengele did.
I work in neurotech/sleeptech and work with Alzheimer's researchers.
This is sensationalist and one-sided.
Alzheimer's is the most common form of dementia, and it is not clearly understood. It is potentially the most common form because it is not understood and there are many, myself among them, who believe that multiple different diseases are being assigned a single title because we don't understand the disease enough.
This isn't to say the Amyloid hypothesis is correct, it may be correct in a number of cases, but the Type 3 Diabetes may also be correct.
The Amyloid Hypothesis has not been disproven. Yes, misrepresented data in a few studies have significantly put into question the reliability, however hundreds of other not "doctored" studies have shown the hypothesis holds significant promise.
The pharmaceutical companies did not make up the format of the disease in order to sell drugs, and the current drugs are not very effective, but that doesn't mean the theory is wrong. Just because amyloid build up is a marker of the disease does not mean that removing this metabolic waste would reverse the disease. That's like saying blowing your nose would cure the common cold.
In the case of AD, the suspicion is that the Amyloid/Tau build up damages the neurons ability to signal within the brain, like a blockage in a pipe that causes the pipe to break. Removing the blockage does not repair the pipe.
So why bother removing it at all?
A researcher we work with has posited a theory (which is fairly new, but I'm not sure she is the first) that amyloid build up reduces the power of delta slow waves, and the related glymphatic flushing of metabolic waste. This is why the drugs might be valuable (I'll say might be, rather than are), increasing the removal of waste slows further progression of the disease.
Having said that, there is a point in time where slowing progression is just lengthening time in poor health, and is not valuable, but prior to that, it can be valuable (I'll leave it up to individuals to decide what is right for them or their family members).
We've been developing slow-wave enhancement technology at Affectable Sleep [1] for the last 5 years, and similar tech has shown early promise in people with AD [2] as well as potential preventative in elderly people [3].
[1] https://affectablesleep.com
[2] https://pubmed.ncbi.nlm.nih.gov/39048400/
[3] https://academic.oup.com/ageing/article/52/12/afad228/750330...
FYI: This topic has been extensively discussed here over a loooong time [1].
[1] https://hn.algolia.com/?dateRange=all&page=0&prefix=false&qu...
The book is new though.
What do doctors prescribe nowadays? Same discredited meds?
How about SSRIs, for which much of the research does not provide supporting evidence? E.g. there's a 2022 meta-study by Moncrieff et al that shows there's no consistent evidence tying serotonin to depression. An earlier 2008 placebo-controlled study by Kirsch et al shows that SSRIs are barely any better than placebo.
IOW, SSRIs are useless horseshit for the vast majority of people (especially in the absence of e.g. CBT) and the theory behind them is not supported by evidence. Why are they still prescribed?
It is now well known that serotonin uptake cannot explain the effect of SSRIs and that we don't actually know how they work- but that doesn't mean they don't work. Most drugs have many effects (we call some of them side effects) and this isn't the first drug where we thought we knew how it worked and ended up being wrong.
Some have found flaws with Kirsh's study and there is still an ongoing debate about effectiveness. [1] I am not a fan of prescribing so many people a drug that we don't know how it even works for what is often just a small improvement, but I don't think its accurate to say they are useless.
[1] https://academic.oup.com/ijnp/article/14/3/405/906146#156821...
I suspect SSRIs would work a lot better if we could select a better cohort for them. My sister comment notes how depression can be a symptom of a more treatable/precise disorder and so Depression becomes a broad church of several disorders when they present mildly or are not diagnosed for some other reason.
I'm not sure in general but there is evidence that some dementia is down to infections and can be treated in the usual way for those - https://www.theguardian.com/lifeandstyle/2024/dec/01/the-bra...
I think I read that amyloid may be a body immune reaction to infection which is why targeting that rather than the infection is ineffective. (not expert on this but the article is interesting).
I suspect SSRIs are prescribed because they are easy to prescribe.
I think they don't work because Depression, like Alzheimer's, is poorly defined.
From a population genetics perspective we can find clear genetic signals for other psychiatric disorders such as Schizophrenia, ADHD, etc. But Depression is notoriously difficult to identify any genetic signal for. Its my opinion that this is because Depression is more often a symptom of another psychiatric disorder and only rarely is the root cause just Depression itself.
Many folks with ADHD, Bipolar, or other "mild" disorders go undiagnosed and get the Depression label instead and this muddies the waters.
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People lambast RFK because, among other things, he thinks that the polio vaccine never protected anyone and has killed more people than polio (https://www.nytimes.com/2024/12/17/health/robert-f-kennedy-j...).
That's what the evidence suggests.
What evidence, exactly?
You must be Zero Mostel reincarnated on the subject of Romanian Jewish cooking.
To be fair, there's plenty to lambaste him for. But that's not the question. The question is, what's to prevent my doctor from prescribing "treatments" that are based on recently (or not so recently) discredited research?
The main thing that RFK worries people about are vaccinations and his anti-vax and anti-FDA stance, that's it. Saying that people are against "healthy eating and meditating" is somewhere between an obviously stupid lie and a misrepresentation you should be ashamed of.
Shame is for people who don't have receipts: https://www.youtube.com/shorts/6r3-mZ25sDI
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No, but the careers and reputation of those who lead this avenue and undermined good science must be conclusively ruined.
We can start by letting the truth come light in stark and unambiguous terms again and again, along with the billions of dollars in damage and hundreds of thousands if not millions of families left to suffer thanks to prestige and fraud.
Better yet, also reward the risk takers then and now; trying to chase good science as hazardous as it was.
Like the former President of Stanford? It took years for him to be given the golden parachute
If the shoe fits.
It’s a big scandal and I suspect researchers in businesses and universities be found complicit; if we have the appetite and headcount to chase it.
I have little tolerance for fraud, and this is an example of why trust in science (the institution) is at an all-time-low.
good news! he's doing a vc-backed startup now
nevermind he's good now
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I know this is a flippant comment, but do you really think this would solve the problem? I feel like this would just lead to academic misconduct never being reported. It is hard enough to get someone to report a fellow academic for fraud when the only consequence is professional reputation; do you really think ANYONE would turn in a colleague when the consequence is death?
Plus, people would be so scared that they will make a mistake that will be interpreted as fraud that no one will want to publish research.
Maybe not "execute" but some real-world accountability would be nice. As in, perhaps, a lengthy prison sentence.