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It's Unexplainable. I'm Noam Hassenfeld. Last year, we made an episode all about Alzheimer's disease. But this past July, new information came out that surprised both me and Unexplainable producer Bird Pinkerton. So for the last month, we've been digging into that story together. I'll let Bird take it from here.
I think I would have liked Julie Goldberg's mom. My mom was a pistol. My mom was happy and she was sharp and she was tough and she was the boss. Dorothy Goldberg was smart, too. My mom did not have really any educational opportunities, but she loved to read. When I was in college and I was majoring in English, I would bring home my books and she'd say, leave those here. But as she grew older...
Julie's mom started struggling with dementia. She lost some of her spatial awareness. She crashed into a parked car. And then she got paranoid. She suspected family members of plotting against her. She suspected the neighbors of plotting against her. Julie says that the specialist that she and her mother went to agreed that this was probably Alzheimer's disease. And Julie was hoping that there might be something out there that could help.
But she is also a librarian who teaches people how to read and parse information about science. So she had done her research and she knew the realities about Alzheimer's disease. She knew that there's no cure, that there aren't really good treatments out there.
And she even knew a fair amount about why. I had read years back that there were kind of two different hypotheses about what caused Alzheimer's and that there was some controversy because people felt that all the research money was going in one direction and that might not have been the correct direction.
We actually covered this last year in another episode about Alzheimer's disease, but since it's a really key idea, we're going to do a quick recap here. So, there are a few hypotheses about what might cause Alzheimer's disease. Some people think it's connected to a virus, for example. Other people think it's connected to a protein called tau. But the main hypothesis that has really dominated the field for almost three decades now is called the amyloid hypothesis.
The basic background here is that there are plaques that are found in the brains of a lot of Alzheimer's patients. And they form when fragments of proteins that are known as amyloid beta all clump together. And amyloid beta protein fragments can also crop up in other parts of the brain and in other forms. So the amyloid hypothesis is that
Some form of amyloid beta is the culprit here. Like, maybe it's the one in the plaques, maybe it's the ones elsewhere, maybe it's all of them. But amyloid beta is somehow responsible for Alzheimer's in the brain.
Except that researchers have been targeting forms of amyloid beta in the brain for three decades at this point, and that hasn't yielded many great results. So that, basically, is the story that Julie knew. And I just thought, oh well, like, bad luck there. You know, like, the funders made poor choices, and that's kind of part of how scientific research and scientific funding works sometimes.
Still, it was tough to live through this in reality. Doctors prescribed her mother pills, but Julie remembers them being ineffective. At one point, she remembers going to a specialist and asking, What can you do for her, really? What can you actually do for her? And the psychiatrist whose job this is saying, not really anything, you know, maybe in 10 years. And it was so disheartening.
In June of this year, Julie's mother Dorothy died at 89. And then in July, an article came out in Science magazine that was making a big bombshell of a claim. This article looked at a key Alzheimer's study from 2006, this paper that had helped shape 16 years of Alzheimer's research, that had helped support that all-important amyloid hypothesis. And this article in Science magazine said,
It's said that this 2006 paper might have doctored evidence in it and that it might show signs of serious misconduct. I was like, that sounds absurd. That can't possibly be true. But the more she read, the more it seemed to Julie that
Maybe it wasn't just bad luck that researchers had spent so many years so focused on the amyloid hypothesis, doing Alzheimer's research that hadn't necessarily led to much. Maybe it was the result of this potential misconduct. And the news outlets reporting on this issue ran with a very similar idea.
A global developing story of what could be the biggest medical scandal in decades. The data behind the most influential theory of what causes Alzheimer's disease may have been manipulated. The study that more than 16 years of research was based on had tampered with the results. And if that turns out to be true, it means about a billion dollars in U.S. taxpayer money used for Alzheimer's research over the past 16 years
may have been for nothing. - How will Alzheimer's research recover from a decade and a half long wild goose chase and lost opportunity to find effective treatments?
Understandably, Julie was really frustrated by all this. I felt like the scientists had potentially robbed my mother and me and our family of years of her life. Because perhaps, and it's not definite, perhaps if the resources had been directed toward the right hypothesis...
there would have been something to help her. Now, she might not still be alive because she had other health problems, but she might have been happier. She might have been less paranoid. I felt robbed and I felt outraged on her behalf. When I talked to the reporter who actually wrote this bombshell piece for Science, though, he basically said that people like Julie, families of Alzheimer's patients, they have every right to be mad about
But the media narrative around his story isn't quite accurate. Like, yes, this study had potentially manipulated evidence. And yes, it does seem like it was an important study. But there is a more complicated and maybe even more interesting story here. So this week on Unexplainable...
What does this bombshell investigation in Science Magazine actually mean? What does it mean for Alzheimer's research, both past and future? And what does it mean for families like Julie's? Well, let me put it this way. I think it would be a mistake to extrapolate out and say because this body of work
is suspect, that it applies to all kinds of other research in the field. As promised, Charles Piller. He is an investigative reporter at Science Magazine, and he spent many months investigating and writing the bombshell piece that came out in July. And Charles says one of the most important moments in this story starts around 2006, when Alzheimer's research was
kind of at a crossroads. Like, at this point, people had already spent over a decade working really hard on the amyloid hypothesis. They had been trying to find ways to clear the sticky, solid amyloid beta plaques out of people's brains. And what they found was that in drug after drug, trial after trial, these techniques of targeting amyloid deposits failed.
A lot of the drugs were doing what they were designed to do. They were attacking amyloid buildups, but they were not really helping patients. They did not improve cognition in a meaningful way, and they did not prevent Alzheimer's disease. So by 2006, there was growing skepticism in the world of research associated with this idea that the amyloid hypothesis might be the key to curing the disease.
So Alzheimer's researchers kind of had a choice in front of them, their crossroads. On the one hand, one option was to start to maybe move away from the amyloid hypothesis, to maybe spend more money on other theories of the disease, like the idea that it was caused by a virus, for example. And that would lead to different experiments and to potentially different drugs. But the other option was to double down on the amyloid hypothesis and to refocus it a bit.
And what that would look like was that a lot of the research up until this point had focused on
the kind of amyloid beta that was in these sticky plaques in the brain. But researchers were getting curious about other forms of amyloid beta that were also in the brain, these more soluble forms, these ones that would dissolve in liquid, basically. And since they hadn't been investigated as much, scientists thought that maybe these soluble forms of amyloid beta could be the future of amyloid research.
So again, it's crosswords. We have people trying to figure out what they're going to do. And this is where our influential, controversial bit of research comes in. It is the work of several scientists, including two important co-authors. Karen Ash and Sylvain Lesnay. Both at the University of Minnesota. Karen Ash was an eminent and highly regarded Alzheimer's researcher. And Sylvain Lesnay was her protege.
a very up-and-coming, promising scientist working in her lab. And basically what Sylvain Lesnay and Karen Ash had done was they had taken one of these soluble forms of amyloid beta... And they injected it into rats. And almost immediately, the rats started to have memory problems. For example, being unable to identify portions of a maze that they had previously learned. That...
were akin in many ways to the symptoms of Alzheimer's disease. Charles says this experiment was actually kind of mind-blowing in the field because it was so clear and almost linear. Like, it showed that you could inject this form of amyloid beta and then see something like Alzheimer's symptoms show up. And even though it was just in rodents, it attracted attention because it was this tidy, causal relationship. Not just a causal relationship, but one that could be demonstrated experimentally.
And that was the key. In this super confusing field, you had this clear, solid finding that suggested that these soluble kinds of amyloid beta were connected to Alzheimer's. And so you can think of this research almost like a neon sign that popped up right next to the crossroads and said, hey, keep going on this amyloid hypothesis path. Like, you don't need to change paths anymore.
There's something here. And that's why this breathtaking study in 2006 kind of turned over the table on Alzheimer's disease and got people thinking about it in a new way. And really, among the skeptics and among those who were discouraged about the lack of therapeutic process, they finally agreed.
realized, wait, this maybe allows us to have more hope in the amyloid hypothesis and how it might cure the disease. I think this is where some of the coverage of all this has gone a bit astray. So I just want to be really clear here. This study is not the only study that has ever pointed researchers in this direction. Other research did eventually come out suggesting that soluble amyloids were a potentially good bet. This is not the foundation on which
all this research rests. But Charles says that this study was really influential. Like, after it came out, funding for research into various forms of soluble amyloid beta exploded. The NIH went from spending a few million dollars in 2006 on this topic
to over 280 million in 2021. Pharma companies have spent billions of dollars developing and doing clinical trials on drugs that tackle soluble forms of amyloid beta. Which I might add so far have failed.
Study after study, trial after trial, drug after drug. And this research from 2006 has also been cited thousands of times. Like Charles says it's one of the most cited basic papers in Alzheimer's research. In other words, it was one of the most important studies as far as how it shaped people's thinking about the field of any study published in the last 16 years.
Which is why Charles was so shocked last year when he learned there might be something seriously wrong with this 2006 research. So, here's how it went. I guess it was late November, early December.
I became connected with a whistleblower. This whistleblower was an assistant professor at Vanderbilt University named Matthew Schrag. And before he reached out to Charles, Matthew Schrag had been on kind of a long research journey. But the short version is this. Basically, two investors decided to bet against an upcoming Alzheimer's drug. They thought that the science behind it was kind of suspect.
So they hired a lawyer. He hired Matthew. Matthew got paid to look into the research around this Alzheimer's drug and see if it had any problems.
And they chose Matthew because he's really good at looking at a particular type of image that comes up in a lot of Alzheimer's papers, this thing called a Western blot, which basically shows you which proteins are in a sample at any given point in time. And so what Schrag is an expert in is looking at these blots
Matthew will look for cut and paste marks, for example, or like weird issues with the background of the blot. It's kind of like the internet detectives who can look at like a celebrity's Instagram photo and tell you all the ways that it's been filtered or photoshopped, but for like key pieces of scientific evidence.
So at first, Matthew was looking for these Photoshop-y things in the research related to this one specific Alzheimer's drug. But then he broadened his search. And...
He continued to try to understand better the extent to which these kinds of problems not only affected that drug, but also other developments in research in the Alzheimer's field. Which is how Matthew Schrag eventually wound up looking at that 2006 research, the research that had been cited so many times. And he wound up analyzing the evidence in it. And when he did so, lo and behold, image after image...
showed signs of doctoring. This vitally important paper, image after image after image, showed signs of doctoring.
In the end, Matthew ended up looking at a whole bunch of different papers. And a kind of pattern emerged where one of the co-authors on this big 2006 paper, this guy named Sylvain Lesnay, he had a lot of potentially problematic work. Matthew wound up looking at around 20 of Sylvain Lesnay's papers overall. And in almost every case, he found image after image, problem after problem.
And because there was this sort of big, broad pattern of potentially problematic evidence in Sylvain Lesnay's work, it was really hard for Matthew and Charles to look at it and say, OK, maybe this was just a mistake in one paper or something. Like, it really seemed like grounds to question that influential research from 2006 and to question its conclusions. I suddenly realized...
that I had something on my hands that I hadn't bargained for, something that could have broad influence in the field. After all, if this was true, then Alzheimer's researchers have been citing a study with manipulated data for 16 years.
Charles wanted to be cautious here. I mean, so far, all I had was this guy at Vanderbilt University who was thinking about this and was concerned about it. So he reached out to a whole bunch of experts, like forensic image experts, Alzheimer's researchers who are invested in the amyloid hypothesis, and Alzheimer's researchers who are skeptical of it.
And he showed them Matthew's analysis of the 2006 study and some of the other Sylvain Lezney papers he'd looked at. And what I found was they were all of one mind about it. Expert after expert, both in Alzheimer's disease and also in forensic image analysis, agreed that Matt Schrag's analysis was cogent, it was clear, it was well-supported, and it raised really serious questions.
They didn't all agree on every single image, but he says that they did agree that something was wrong or something was fishy about many of the images that were presented as evidence in these papers. Whether it's fraud, you have to go to intent, and I don't know what was going through the minds of these scientists at that time. I think what I would call it is apparent misconduct. But now Charles was left with more questions. Like, if this misconduct happened...
Why did it happen? And what would it mean for Alzheimer's research? After the break, we'll actually speak with one of the co-authors of the original 2006 study and try to get some answers. Support for Unexplainable comes from Greenlight. People with kids tell me time moves a lot faster. Before you know it, your kid is all grown up. They've got their own credit card.
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The Walt Disney Company is a sprawling business. It's got movies studios, theme parks, cable networks, a streaming service. It's a lot. So it can be hard to find just the right person to lead it all. When you have a leader with the singularly creative mind and leadership that Walt Disney had, it like goes away and disappears. I mean, you can expect what will happen. The problem is Disney CEOs have trouble letting go.
After 15 years, Bob Iger finally handed off the reins in 2020. His retirement did not last long. He now has a big black mark on his legacy because after pushing back his retirement over and over again, when he finally did choose a successor, it didn't go well for anybody involved.
And of course, now there's a sort of a bake-off going on. Everybody watching, who could it be? I don't think there's anyone where it's like the obvious no-brainer. That's not the case. I'm Joe Adalian. Vulture and the Vox Media Podcast Network present Land of the Giants, The Disney Dilemma. Follow wherever you listen to hear new episodes every Wednesday. One of the most influential studies in Alzheimer's research may have been... The Unexplainable Podcast from Vox.
So here's what we know. In 2006, a study was published that helped shape Alzheimer's research. Basically, it helped keep the field focused on the amyloid hypothesis at a time when people were starting to consider other options. That research has evidence that seems to have been doctored. It has images that show signs of copying and pasting and other problems.
And so the host of Unexplainable, Noam, and I, we reached out to Sylvain Lesnay and Karen Ash, two of the main co-authors on the 2006 paper, just to try and understand why this had happened. Sylvain Lesnay did not respond to our request for comment. The University of Minnesota did, saying they were following a review process and couldn't comment further. But Karen Ash did agree to speak with us.
I'm Karen Ash. I've been studying Alzheimer's disease and neurodegenerative diseases for the last 35 years. Karen did lead the lab that this 2006 research came from. But just to be clear, in Matthew Schrag's analysis, her other work, her studies that don't involve this co-author, Salma Leznei, that work seems to be clean and without doctoring.
So Noam and I were asking her specifically about this 2006 research with Sylvain Lesnay. I want to just ask you about what Charles raised in his piece, which is the contention that in the 2006 paper and then in other papers, there were signs that the Western blots were either tampered with or maybe there were cloned backgrounds that were merged together and bands moved around. Do you see any validity in those claims?
Well, there's universal agreement that the issue he raised is serious, and it simply shouldn't happen. But while she acknowledges that there were some potentially altered images, Karin Ash does disagree with some of the issues that Matthew Schrag found with the 2006 research. On this particular paper, most of the images
The flagged figures, the majority of them were like printing errors. And only two of them were really examples of altered figures. She also maintains that the science at the core of the paper is still valid. Well, in this case, the...
editing of the images was in regions of the blot that was unrelated to the data related to the experiment itself. And so the conclusion from looking at that blot was unchanged.
She told us later by email that she doesn't have access to the original blot images, but she personally observed a lot of them as they were hot off the presses or sort of developing. So she is confident because of that that if the images were altered, it didn't alter the conclusions of the paper. This is where Noam and I push back a bit. If they didn't alter the conclusions, do you have any reason to suspect why they might have been edited?
You know, I keep asking myself over and over again, and I've asked the individual who was responsible for generating the plots, and I've not received an answer. And I guess when I hear of results being positive,
you know, tampered with, manipulated in some way, I think that, oh, there must be a reason behind it. And that reason seems reasonably to assume that it's to demonstrate a result that may not have been there otherwise. So what is the case that this is still valid? Like, why wouldn't tampering of images invalidate the results? Well, in this case, the
editing of the images was in regions of the blot that was unrelated to the data that the experiment was intended to, well, it was unrelated to the data related to the experiment itself. And so the conclusion from looking at that blot was
unchanged. Sorry, if these regions were tampered with, these images, and they were not in regions that affected the results, there seems to be no reason to tamper with those images. Those images, it seems like what you're saying could be any images because they wouldn't have affected the results. Yes. I guess it doesn't seem clear to me how the results could be unaffected by manipulated images.
Well, I have to say that I don't understand why the images were altered. It seemed to me as though they were cleaning up or making the blots look a little better in the sense that they were cleaner, but it did not alter the conclusions
of the paper or the conclusions of the experiment itself. - Okay. - And so I think it's a puzzle to me. I think it's actually very sad that this happened.
I spoke with a forensic analyst who looked at the images for Charles, and she said that she wouldn't trust any paper that had altered images because images could just be the tip of the iceberg. It's much harder to spot alterations in a bar graph, for example, where you can just delete a number and pop in another one. So if there's an altered image in a paper, even if it's just cleaning up, it could be a sign that other data has been altered.
Nevertheless, Karen stands by the conclusions of her research so firmly that she actually thinks more money should be invested into the specific kind of amyloid beta that she tested with, which she referred to as a type 1 oligomer. So I asked her about that. I hear what you're saying about there are printing errors. I hear what you're saying about, like, you still feeling confident about the central result that was generated. But I think I would be hesitant to
Personally, if someone said to me, there is this 2006 paper and it has potentially flawed images, but it holds up, I promise. And it's this type one oligomer. So we should invest in oligomers.
with type 1 oligomer, maybe that's the future. Do you understand, I guess, where I'm coming from on my hesitation there or my sort of confusion? Yes, it's absolutely understandable. And as I said earlier, there is no consensus on what to do when this happens.
So some people, as I said, think you just throw the whole thing out and start all over again. And other people say, wait, you know, did these alterations really change the basic fundamental conclusions? And it is a complex problem. No two cases are alike. And it needs to be evaluated carefully.
Karen Ash is correct that there is little consensus about what to do next, but Charles Piller says that most of the researchers he spoke to for his piece, they start from the assumption that if this paper does have altered images, it shouldn't be relied on scientifically.
He says that what they actually disagree on is what these potentially altered images mean for how to move forward with other research. There were different thoughts about that. Some people do take a really hard stance on what these signs of misconduct in this paper mean. One of the experts who I consulted with was a guy by the name of Tom Sudoff at Stanford University. He's a Nobel laureate.
And his view was that the ramifications were wasted thinking, wasted effort in the field. When I first read the science article, I thought something like this. I thought that these potentially altered images could mean that 16 years worth of Alzheimer's science was pretty misguided.
That's sort of what the media narrative around this has been. I think it's what Julie, the woman whose mom had dementia, I think it's what she thought too. But there has been a fair amount of pushback on that view because researchers who spent a long time working on amyloid beta research, they say something like... It's terrible that someone might have falsified research that has been influential. But regardless of that,
It's not important. Basically, sure, like, maybe this paper was a signpost that helped point research in a new direction. But it's not the foundation on which all their research rests. Many of them are not even researching the exact same kind of amyloid beta as the one in the 2006 paper.
So not only were the last 16 years not a total waste of time, but also, some people say, we should stick to the amyloid hypothesis. Everything's fine. Let's just keep on track. Charles understands where these people are coming from. I have great respect for many of the scientists who have been exploring amyloid hypotheses.
reasons behind Alzheimer's. I have great respect for the work that they've done, and I think some of it may still be fruitful and important. I'm not suggesting that it's all junk and this dispels all of it. But he says that there's a middle ground here, like a place in between dismissing the last 16 years of research as junk science and saying, oh, no, everything's fine, and we should just continue to invest in the amyloid hypothesis.
This exposes something that's critical for the amyloid research community to look at carefully and to kind of rethink their position. In this line of thinking, this potential misconduct should be like a wake-up call. Because if this paper was being cited, giving people confidence that they were headed in the right direction—
And now, 16 years later, researchers are not any closer to solving Alzheimer's, then... Why not use this as an opportunity to take a good hard look in the mirror and ask some basic questions? Are there areas of research that we have neglected because of the dominance of this idea in the amyloid research world?
that now should be reinvigorated and rethought. Scientists have spent hundreds of millions of dollars and three decades on different versions of the amyloid hypothesis, chasing different kinds of amyloid beta in the brain. And that investment hasn't really paid off. They don't have a cure or really good treatments to give the millions of people suffering from Alzheimer's.
So maybe the discovery of these potentially doctored images could be a reset button here, like a moment to say, okay, it's time to shift a lot more money and a lot more time into other hypotheses. At the tail end of pulling this story together, I called up Julie Goldberg again, the woman whose mother suffered from dementia.
And I told her about this conversation that I'd had with Charles, basically this idea that the potential misconduct in the 2006 paper didn't totally invalidate 16 years' worth of research, that it wasn't quite as bad as the TV stories might have made it seem.
I don't think this changes. It doesn't change the story all that much for me. I'm certainly glad to hear the news that you're telling me that it maybe wasn't quite, didn't have quite as much of a negative impact as it initially appeared. But ultimately, I think my frustration is the same, that somebody took advantage of the system. And had they not done that, we
we might have been further along than we were. I just know there were no treatments and there were no cures. So I don't feel qualified to wade into the last 16 years of research and to sift through and figure out how much of it was a waste of time and how much of it contributed to basic science and to developing treatments. I know that for my mother, there was nothing.
Julie is pretty clear about what she'd like to see in the future, though. She says she'd like to see the field of Alzheimer's research change.
And that's what gives her some hope in all this. Well, I guess, I mean, it gives me, I mean, if we're going to stop chasing the wrong hypothesis and throwing billions of dollars at it, yes, I have hope. Probably more hope now than there's been any time in the last 15 years. But, you know, that hope could have gotten here a lot sooner and maybe soon enough to help my mother.
This episode was produced by Bird Pinkerton and me, Noam Hassenfeld. It was edited by Meredith Hodnot, Catherine Wells, and Brian Resnick. Meredith did some amazing clipwork, too. I wrote the music, Christian Ayala handled mixing and sound design, and Serena Solon did our fact-checking. Huge shout-out to Serena, because this was definitely a complicated one. Thanks also to Elizabeth Thicke for her time, and to Manding Nguyen, who's off somewhere dreaming of electric pigeons.
If you want to hear more about Alzheimer's research and the amyloid hypothesis in particular, check out our episode from September 2021. It's called What Causes Alzheimer's? You can find Charles Piller's reporting in Science Magazine. The article is called Blots on a Field, and it's definitely worth a read. Derek Lowe's follow-up piece, Faked Beta Amyloid Data, What Does It Mean?, is also really helpful if you want more information.
If you have a minute to leave us a review or a rating, we'd love that. We'd also love to hear from you. We're at unexplainable at vox.com. Unexplainable is part of the Vox Media Podcast Network, and we'll be back next week.