How Fraud, Greed and Negligence Have Stymied Alzheimer’s Research and Progress Toward a Cure
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From KQED in San Francisco, I'm Alexis Madrigal. What if a large chunk of the Alzheimer's research that's come out over the last 25 years is based on widespread fraud?

That's the shocking thesis of a new book by journalist Charles Piller. Working with neuroscientists and misconduct investigators, he compiled thousands of doctored images from many prominent labs. There are so many problems now in the scientific record that they suggest that a leading theory about Alzheimer's might need to be massively revised. We talk with Piller about his new book, Doctored, Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's. Coming up right after this news.

Welcome to Forum. I'm Alexis Madrigal. This new book doctored by our guest this morning, Charles Piller, is a real stunner. With meticulous and grueling investigative journalism, Piller demonstrates that large chunks of the Alzheimer's research world are rife with fraudulent data, often in the form of images that have been spruced up to tell a false story.

Most of the problems emanate from people working inside the dominant Alzheimer's disease paradigm, which holds that the disease is caused in the main by the buildup of particular proteins in the brain amyloid plaques.

The problems with the research Pillar documents are so severe that, along with other evidence, they suggest the field's due for a paradigm shift away from that model of the disease. Here to walk us through his findings, we've got Charles Pillar, the author of Doctored, Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's. Welcome.

Thanks very much, Alexis. So let's first talk a little bit about Alzheimer's, how many people it affects and kind of the difficulty of getting a handle on what it actually is.

Well, Alzheimer's afflicts about 7 million people in the United States. And I think it's important to remember that the whole community of people that the disease affects is way, way larger because many, many, many of those people are cared for by family members, other loved ones, neighbors even. And the population is just gigantic of people that have their lives really dramatically affected by the disease. There's also something about

Alzheimer's kind of robbing people of their own sense of self that I think is particularly terrifying to some people such as myself when I think about this. Like many other diseases of the brain, though, it's like immensely complex, right? I mean, tell us more about sort of how we think or what we see in the brain when someone has Alzheimer's.

Sure. So you're absolutely right that Alzheimer's, I think, is perhaps the most terrifying of all ailments because, again, it starts with subtly stealing memories and abilities to do everyday life kind of activities and then goes on to actually deteriorate.

take apart someone's sense of self, as you say, in a way that people just are terrified by, as you say. This disease is so complex in part because the brain is so mysterious. If you look at other major killers,

things like heart disease and cancer, there are many remedies that have been very effective at reducing death rates, particularly in developed nations. And everything from chemotherapy to drug, other kinds of drugs, healthy lifestyles even, radiation, all kinds of approaches to

cure or at least reduce the severity of those illnesses are present. Not so with Alzheimer's disease. And I'm sure we'll talk a little bit later about some of the drugs that have come to market to treat Alzheimer's. But we don't have anything that either arrests or reverses the symptoms, nothing. And so that in itself is also a terrifying aspect of the disease.

Also, as people have been living longer, right, Alzheimer's becomes kind of a bigger share of the pie, right? If people aren't dying of cancer and heart disease, then a larger number of people are reaching the kind of ages when Alzheimer's becomes more prevalent. Exactly right. And in fact, if you'll permit me to go back to the beginning, more than 100 years ago, when the disease was discovered by a German scientist,

This was a very, very unusual syndrome because relatively few people at that time, back in the early 1900s, lived to old age when Alzheimer's symptoms become much more prevalent. Of course, there are early onset victims of Alzheimer's disease, but those are relatively few compared to the vast majority of people who get the disease. And so what happened is, due to amazing medical advancements over the decades, we

More and more people now are living to old age. Consequently, the rate of Alzheimer's disease and the rate of Alzheimer's deaths, unlike heart disease, unlike cancer, has been rising. And that's purely a demographic fact.

As this has been happening, people have tried to come up with some sort of theory of the disease. And one of the things that scientists notice, right, is that people with Alzheimer's seem to have this buildup of proteins, these sort of tangles in their brains. And this sort of led to this amyloid theory, right, for the disease. Tell us more about how that developed. Yeah.

Sure. So this is, again, going back to the genesis of the discovery of Alzheimer's disease by this German scientist named Alzheimer. And what he did is he was both a pathologist who does autopsies and a clinician. And one of his patients, who was very, very much suffering from dementia, dies and he autopsies her brain. And what he finds are these

heavy deposits of something called amyloid plaques. These are the kind of archetypal sticky plaques that people talk about with Alzheimer's disease. And also, as you mentioned, tangles, these are another type of protein called tau. And these proteins are actually within the brain cells, whereas the plaques are outside the brain cells.

And consequently, Alzheimer's was defined as a combination of these plaques, tangles, and dementia. Now, the hypothesis, the so-called amyloid hypothesis, is really pretty simple to understand. It goes like this. These amyloid plaque deposits give rise to a series of biochemical changes in the brain that lead to Alzheimer's dementia. Okay.

And so the sort of obvious next step, which many scientists wanted to take, is, well, what if we got rid of the plaques? What if we got rid of the tangles, right? Yeah. So...

Back when the demographics of the disease were changing radically, a lot more people were growing old enough to become patients with Alzheimer's disease, and a lot more money and time and mindshare, you might say, of the scientific community went into trying to solve this problem. There was an enormous amount of effort that went into understanding how this biochemical process began to operate. And

What happened was they launched on what was a totally logical project. Of course, since we know that amyloid plaques and other forms perhaps of amyloid proteins

are kind of the culprit here. What if we just develop drugs or other treatments to remove those from the brain? Wouldn't that be a logical place to proceed with this project of curing Alzheimer's disease? And so over time, they were very successful at doing that. They were able to, even early on, we're talking like in the late 90s and then in the early 2000s, they had come up with not just antibiotics,

antibody drugs that remove the plaques from the brain. And antibodies, people may remember that our body produces antibodies to fight off viruses, bacteria. Mm-hmm.

Also, you can create these artificial antibodies in the lab that you can inject into a person, and then they do a similar job, but they don't stimulate the immune system to operate on its own, that you have to get repeated injections of it. And so this process was very successful at removing these amyloid proteins from the brain, but not successful in...

arresting cognitive decline or let alone reversing the symptoms of Alzheimer's disease. So it's very discouraging. Well, and particularly discouraging because it seemed like such an obvious thing to do. Many people had committed, many labs, as we read in the book, had committed so deeply to this theory of the disease. And it's at this point when

maybe the amyloid plaque theory is beginning to lose some luster that we encounter one of the labs supposedly doing groundbreaking research to

I guess, fortify the amyloid thesis. Tell us a little bit about why that was so important. Sure. So we're talking about the year 2006. And at this time, there had been failures in treatment of Alzheimer's using these special products that would remove amyloids from the brain.

And then a very clever, interesting experiment was done. This is a lab experiment with animals in the University of Minnesota. Also, some other institutions were involved, but it was primarily a couple scientists at University of Minnesota. And what they did is they worked with a genetically engineered mouse that was built to produce copious amounts of amyloid in its brain. Then they

targeted a specific type of amyloid protein. So amyloids are a class, amyloid beta proteins is what they're called. They're really a class of protein that has different forms based on the so-called molecular weight of the type of amyloid that you're talking about. And they found one that they called

amyloid beta star 56. They're star protein. So kind of a catchy name that actually helped them grab a little bit of mind share in the scientific community. And then they

supposedly purified this, injected into rats, and found that the rats had symptoms of memory loss that they compared to memory loss in Alzheimer's disease. And so why was this important? Well, a couple reasons. One, it was thought to be the first specific substance that showed a kind of cause and effect relationship between amyloid proteins and memory loss in an experiment. And secondly, it was published in

One of the most prestigious scholarly publications in the world. And this paper became the talk of the town in science. It became one of the most cited experiments in science.

Alzheimer's research for many years subsequently, cited thousands of times. In fact, some of the leading scholars in the field cited this paper over and over and over to support their own assumptions and work associated with the amyloid hypothesis. Because it meant that they could target this specific version of the protein, right? Like maybe taking out the plaques in general didn't work, but there could be versions of the protein that would be disease-causing that they could then use as new targets, right? Exactly right. And in fact,

it caused a kind of renaissance in the way in which scientists thought about the amyloid hypothesis and they focused on these particular form of amyloid, not just the plaques, but also these soluble forms of the protein that float around in the brain fluid that bathes your brain.

they tried to target those specifically. - And not to leave people on a cliffhanger, but there was a problem with the research. We're talking with Charles Piller, investigative journalist with Science Magazine about his long quest to understand what was going on with Alzheimer's research.

His book is called Doctored. Of course, we'd love to hear from you if you have a loved one with Alzheimer's. What have your family's calculations been? But whether or not to use medications or how to seek treatment, the number is 866-733-6786, forum at kqed.org. We'll be back with more on this research problem right after the break.

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Welcome back to Forum. I'm Alexis Madrigal. We're talking with Charles Piller, an investigative journalist with Science Magazine, about his new book, Doctored, Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's. Before the break, we were talking about a key bit of research that was done at the University of Minnesota in 2006, which had identified particular forms of protein thought by some to cause Alzheimer's.

And we're saying that there turned out to be some problems with this research, which became heavily cited by many people. What was wrong with it and how'd you find out? Okay. So let me just take one small step back and say that at the time this research was published was a time of growing skepticism about the M-light hypothesis because there had been failures in therapies associated with that idea. And so...

It was something that reinvigorated the field. And also, it wasn't alone in doing that. There were other studies that had not the same, but some hints of similar things going on. And so the federal government started to just dump money into this particular way of looking at it with these soluble forms of amyloid protein as a new target. And over time, billions of dollars began to be spent on

on this. So fast forward now to 2021, and I was beginning to look closely at the Alzheimer's question, actually associated with a completely different set of experiments. It was about a drug called semufilam by a company called Cassava Sciences. That is another long story. We'll get to that. Okay. And so...

Pursuant to that, I was talking with a guy by the name of Matthew Schrag at Vanderbilt University who kind of on his spare time, not associated with his university job, had become a forensic image sleuth. So he was looking for integrity questions in his chosen field. Which basically, I mean, just to simplify for people here.

Busy looking for Photoshopped images. Like, did people create the evidence that they wanted to see in their experiments? Exactly right. And in fact, people should understand that in Alzheimer's disease, there's a couple kinds of images that...

that are critical to understanding the experimental outcomes. One is these things called micrographs, which are just basically highly, highly enlarged photos, usually of brain tissue. And then the other is something called Western blots, which are a way of showing the presence and type of amyloid proteins in a tissue sample. Very important in order to know what you're looking at and what might be causing an effect. And

These are both photographic techniques that, as you say, can be photoshopped. Yeah. They also look... People are trying to imagine, right? It almost looks like a sonogram or something, right? I mean, there's just like a little bit more material in this sort of rectangular grid in places where you're looking for particular proteins. And so...

If you wanted to doctor an image to say show that there was more protein in one place rather than another, you could literally take it from one area, hit copy, and drag it over and hit paste. That is exactly right. It kind of looks like a ladder, kind of like stacked irregularly shaped bands. And the size and intensity reflect the amount of protein it's detecting. Mm-hmm.

And as Schrag started to do this work at Vanderbilt, you know, looking into various different research groups, you stumble, maybe not stumble, but find this 2006 work. And what do you find in it? Like, is it just that a

a couple of images look like this and a couple of papers? Are there other explanations for this aside from fraud, I guess is what I'm asking? It's a very good question and of course one that as an investigative reporter I had to sweat that very carefully. So what happened was Schrag began to see irregularities in images associated with a particular scientist at the University of Minnesota who was one of the key authors of this 2006 paper.

At first, he didn't.

see the 2006 paper, he saw these other papers that had apparently suspect images. And then he did some more digging around into the guy's history. The scientist's name is Sylvain Lesnay. And he found this 2006 paper in the portfolio. And of course, he knew immediately how important this was because this is Schrag's field. He knows that this was a seminal paper in Alzheimer's research. And

And so he said, "Okay, I'll take a look." And he went to examine those images in the paper, these western blots and micrographs, and tried to understand whether there were reasons to doubt the veracity of these images, just on the basis of understanding that there were suspect images in other papers by the same guy. And lo and behold, he found really clear evidence of doctored images in this important experiment.

I want to zoom out pretty widely here now. We found this one set of papers, this one set of scientists. That'd be one thing, you know, a bad actor. I mean, uncontrollable, more or less, in a widely dispersed scientific enterprise. Someone could go cheat, right? I mean, many people say that to you in this book.

But as you develop this investigation, you found dozens of people who did similar things, it appears. And more importantly, almost like the toxic assets of like the financial crisis, those papers are cited by all these people, which means that this fraud ends up running through a huge chunk of the enterprise, right? Yeah.

Yeah, I'm afraid so. Let me just say quite clearly, though, that I believe that the vast majority of scientists in this field are completely honest and deeply determined to do work that is of great integrity and oriented fully towards solving the problem of Alzheimer's disease.

But like any walk of life, there is a certain small percentage of people who are willing to cheat and willing to cut corners or sometimes engage in outright fraud for either financial or professional reasons. It's a hyper-competitive field. It's a field where publishing provocative results can mean the difference between a mediocre career and a great career.

And because Alzheimer's is a field where there's a lot of confusion about what's going on scientifically, sometimes false results can stand for a long time. Not only stand, but be widely cited and lead us in research directions that maybe were not as productive as they might have otherwise been. That's right. And I think Shrag said, I think pretty well, he said that even a small amount of

image doctoring in important papers that are strategically placed can skew thinking in the field. And he's not the only one to say it. I've spoken with many scientists who agree. They're all identified in the book as well. So it's a problem that can, as you've, I think, suggested, grow out of proportion even to the specific number of studies that were obviously doctored. Of which there are far too many on the basis of the book. Yes.

I want to ask a couple of questions about the sort of situational importance of this. Reading this book in this particular moment,

I was thinking there are a lot of people who are really opposed to the enterprise of science right now. Do you worry that some of those forces will see this and say, yeah, look at that. We should defund NIH, the National Institutes of Health, because they're full of it? Well, in a word, yes. I'm deeply concerned about that because I think that would be the worst possible outcome for

Let me put it this way. Where I have common ground with people who are critical of science is that I think some of the institutions of science have been complacent about this problem of apparent image doctoring and possible even fraud in the field for a long time. And when I say the institutions, I mean the jurisdictions.

journals, the funders, the regulators like the Food and Drug Administration, and the universities, they've all kind of taken a lackadaisical attitude towards the importance of identifying and correcting false images in scientific papers. And so where does that leave us? Well, I think basically where it leaves us is that this is an opportunity now for the

institutional authorities to take a good hard look in the mirror and say, how are we going to clean up our acts? How are we going to police this effectively in a way that preserves what is so important, which is most of science, without it being attacked by anti-science forces, either out there in the media world, in the populist world, and also inside the new administration. Yeah.

I mean, do you think that lackadaisical attitude resulted from essentially people being completely tied up by conflicts of interest? And so they kind of didn't want to know what they didn't want to know? Yeah.

I think that's part of it. I think really the complacency comes partly from these are institutions that view each other as sort of colleagues. In other words, there's a kind of inherent sense of trust that makes it unseemly to suspect your colleagues of having faked some data. And even though they know it happens, it seemed that people are kind of squeamish about it in a way. The other is that the bureaucratic process

process for investigating allegations of misconduct in science is horrifically slow and often very ineffectual. And so I think people who are

are dishonest might be prone to roll the dice on doing something provocative that could help them advance in their career because they see all around them that even people that get caught faking data sometimes don't have very big consequences. I mean, not to take the side of people who have fake data, which is obviously wrong, but one part of me as I read this book was thinking, these people must really believe that

That this that what the experiments they're doing are important and that the results are almost there or would be there or should be there. And I think people kind of forget how much of a lab science many things in biology still are, you know, where there's little technique differences can make a huge difference.

in the outcome of experiments. And so do you think it was that people basically thought, well, I'm right in general and this experiment should have worked, therefore I should fake the data so that it comes into alignment? Yeah, well, I am not a psychologist, so I'm not going to diagnose people. But I want to say that you can see a pattern here.

So it often starts with the so-called beautification of images. In other words, making little tiny changes to an image that give it more curb appeal for journal editors. Again, publish or perish, very competitive to get your papers, especially into good journals. And so beautifying an image, it's frowned upon, but it's not regarded as misconduct. Then there can be a slippery slope where someone would then say,

"I think I got this result. It's very, it's a weak showing of it in this image, but I can just sharpen it up a little bit and what's the harm because I know I got a good result."

Or then it can go proceed down that path where someone says, I feel deeply that my instincts on this are right, that the experiments are headed in the right direction. I'm not seeing it in the data right now, but I'm just going to display it that way because I think that'll be to everyone's ultimate benefit. That's, in a way, even a charitable view. Some people are engaging in stuff that they know is wrong. Yeah. Let's bring in John in San Francisco. Welcome, John. Hi.

Hi, I have a quick question. So much of the research these days, even when done in credible academic institutions, so much is supported by money from drug companies or medical equipment manufacturers.

And many of these academic researchers are very credible, but they receive so much compensation from these companies, either speaker fees or research funding and whatnot. And my understanding is the majority of the clinical research these days actually is supported by companies, drug or manufacturer companies, and not the NIH or public health service anymore because of reduction in funding. So my question is, even though

there are some safeguards like the Sunshine Law and whatnot, but usually there's so little transparency, number one. And secondly, even when the associations are being disclosed under the Sunshine Act by these researchers, the fact that some of them are receiving substantial amounts of money, and I'm not talking about a few thousand dollars, could be thousands of dollars and some even more than that,

every year. How much of a concern is that in terms of the financial influence and pressure on their research? And what, if anything, can be done about it? Yeah. John in San Francisco, thank you so much for that question.

There's a lot of this. Answer John's question first, and then I have a follow-up. Okay. So the short answer is yes, that's a serious problem. And the money is huge too, particularly for some of these drugs, right? I mean, people spin something out of their lab and might get funding of hundreds of millions of dollars. They even take companies public and the stock is going up and down. They can sell on highs. There's a lot of specifics to this. Absolutely. I mean, there's two kinds of issues there. One is that

Some of the physicians and scientists who work on these studies get

payments to be experts for the companies, to advise them, to speak for them, etc. And some also get money for doing clinical research. And these are really different from each other, but they both represent potential conflicts because even when you're just getting money to run an experiment, you develop an interest in the success of that process and you become, in essence, an advocate for it, or often you can become in that way.

Here's my question, though. I get that there are problems with having commercial entities funding lots of research, and I think those are sort of well-documented. The thing that blew my mind in this book is you have these companies making bets that are hundreds of millions of dollars, different pharma companies. And it seems like, to me, the very definition of due diligence, like for an investor, to see if the images are faked or not,

And I mean, do we have any evidence that they're looking at these at these research integrity efforts and saying, like, maybe we shouldn't make a bet on papers that have been that have doctored images in them? I mean, if you want to push something through the field quickly and, you know, reform it quickly, it seems like not funding the people who fake the images would be the fastest way to do it.

You know, strangely, there's a lot of complacency even among companies that are spending all this money. Wild. Not always, but...

Well, let me give you one sort of interesting example from a... This is in the book and a story I did also about this for science. And this involves an investigator by the name of Eliezer Maslia, who until recently was one of the most important, powerful officials in the country on these neuroscience research questions. He was the Neuroscience Division Director at the National Institute on Aging, which is the big funder. And he was brought in

at what he called the kind of golden age of Alzheimer's research, ushering that in back in 2016 when Congress devoted a lot more money to these problems. And so as part of a doctored approach,

with the not just assistance but with the incredible efforts of four different forensic image experts. I looked very, very closely at his body of work and found that he had been doctoring images in massive numbers of his papers, a very influential guy academically as well as in the drug field and, of course, as a leader in the scientific infrastructure for neuroscience. And

they developed a 300-page dossier on 132 of his scientific papers, many of which had been quite influential. I mean, some of these cited like in thousands of times. That's exactly right. It was utterly shocking. Now, the reason I raised him in this context, aside from the fact that it

It shows the complacency of the federal agencies that posted him at one of the top jobs and doesn't even have a mechanism for checking out the veracity of people at that level, or apparently doesn't. So one of the reasons I raise him is that he was the developer of basic science behind drugs that are licensed for use in the European Union and...

for drugs that are being developed by an important biopharma company in the United States. And these studies underlying the drugs were based on really clearly clear evidence of doctored images. Now, those studies, when I exposed them in the pages of Science Magazine, the company pulled them off their website immediately.

We're talking with Charles Piller, investigative journalist with Science Magazine, about his new book, Doctored, Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's. We're taking your calls as well to 866-733-6786. When we come back, we're going to talk about how this has played out in treatments. I'm Alexis Madrigal. Stay tuned for more.

Coming up in the next hour of Forum with Mina Kim, just a few years ago Donald Trump said that cryptocurrency seemed like a scam. But after taking tens of millions in donations from the industry and making big investments in the technology, not to mention launching his own coin, Trump is calling himself the first crypto president. We'll look at why that's raising concerns from ethics experts and even crypto industry leaders.

To listen to any Pat's Forum show, go to Spotify, Apple Podcasts, wherever you get your podcasts, and search KQED Forum. Welcome back to Forum. I'm Alexis Madrigal. We're talking with Charles Piller, investigative journalist with Science Magazine. He's got a new book out called Doctored, Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's.

We've been talking about the way that images or the number of images that have been doctored. Listener Greg writes in to say, you know, ask the guest for specific image processing techniques applied to raw images that he classifies as image doctoring. Image sharpening, for example, is widespread across many scientific fields. What precisely are we talking about?

Okay, well, that's a good question. So here are a couple things that are done frequently in apparently doctored images. One is erasing features using the erasure tool in a program like Photoshop. If they are inconveniently contradicting the apparent experimental findings, one is moving features of an image from one place to another to accentuate certain findings. And one is duplicating features

of an image in other locations in the image in order to show that it is more common in that piece of, say, brain tissue than otherwise would be true. And I mean, there are innumerable examples of this in the book, Greg, out there. You know, people being able to compare exactly the

The features, you know, the data that's represented by these images and showing that they have just absolutely improbable levels of overlap, like 99.9% overlap. So there are these things. I want to make sure we get to how this is actually played out in bringing drugs to market. There is a drug called Lekembe, right? Lekembe, which is...

been approved by the FDA, despite the fact that the FDA advisory board

voted not to approve it. How does that relate to this body of suspect research that you're writing about? Okay. So let me just back it up a tiny bit because there was a precursor to Lekembe, a drug called Adjuhelm. That was actually the one that the FDA advisory committee said, do not, do not approve this drug because it's not efficacious and it is potentially dangerous. And

Lekembe was a successor to that. And when the FDA considered that, they got rid of the old advisory committee and brought in people who were mostly very supportive of that direction, some of whom had financial relationships with the companies that were involved with it. So this was a different set of circumstances. But

One of the things that I try to cover in some detail in the book has to do with how the amyloid hypothesis has dominated scientific mindshare for many years, for decades. And this drug, Lekembe, is a product of that. It's a drug that removes certain amyloid proteins from the brain. It's an antibody drug.

So it is infused into a vein, and then it attacks these amyloid plaques and also this other form of some elements of this other form of amyloid protein in the brain, takes them out. And then the patients who are in the trial associated with this before its approval are

were tested against people who had a placebo. So how do you even test people for cognitive effects of a drug? Well, what you do is you give them a series of... It's like a questionnaire that is managed by a clinician, but it involves observations of the clinician, perceptions of the patient, and also sometimes even family members get involved in giving their perceptions of what's going on. There's a lot of subjectivity to it. And so...

You have to have a very large study with a lot of patients in order to have any statistical validity to it. But even then, there are some questions about the validity of this way of testing, but it's widely accepted in the field. And what they found was that this drug Lekembe and another lookalike drug that's been more recently approved, what they do is they reduce the rate of cognitive decline in

from Alzheimer's disease to a statistically observable amount. So let's unpack that a tiny bit. What that means is that no one is having their symptoms arrested. All the patients are continuing to decline cognitively.

But the people on the drug were declining a tiny bit less rapidly than those who were on the placebo. So what do I mean by a tiny bit? Well, what I mean is that it was a level of difference that was small enough that many neurologists and many family members and many patients would not find it to be observable. In other words, it was small.

statistically significant change, but not necessarily a clinically significant change, something that would be clearly an advantage in a patient's life. And that was the pivotal thing. What are you getting for a drug? And it was, these drugs are also incredibly expensive. What,

Why would someone take one of these? I mean, I guess in part it's that there aren't really other drugs out there, right? I mean, this isn't something where you have a range of options and this is just one. There are drugs out there that treat certain Alzheimer's symptoms, for example, insomnia or anxiety, and they can be effective at least for a time.

The problem has been there haven't been these so-called disease-modifying drugs. In other words, drugs that are beneficial for the cognitive symptoms of Alzheimer's disease in a direct way that have been brought to market and obviously approved by FDA. And these are among the first. And so it's so important that...

for the industry to kind of review where we stand with this. There are many people, doctors and drug companies and others, who say this proves the validity of the amyloid hypothesis of the disease because these are drugs based on that hypothesis. There are many others who say, hmm, this is a pretty lackluster result for billions of dollars being spent over decades

If this is what the benefits are, it's not very hopeful for patients and families. Certainly for the idea of a cure or something. Not even close. Yeah.

Well, give us some hope here, Charles. Are there other – let's say that the amyloid hypothesis has been crowding out other promising treatment pathways. Are there things now that you think could get more funding and attention if they're not starved out by the amyloid hypothesis? Yeah.

Yeah, fortunately, I do think so. And thank you for that question. There are a couple of things that I think people should keep in mind. One is that there are very interesting, promising lines of research for other ways of looking at the disease that we might have pretty concrete information of their efficacy in a year or two or three. And so one of those, interestingly, is the GLP-1 inhibitors, the

Drugs like Wegovy and others that are used for obesity and diabetes but are also being found to be potentially effective for all kinds of other stuff, including possibly Alzheimer's disease. There's just a study in Nature that just came out a few days ago that is fascinating and shows an association between the use of these drugs and obesity.

What do you make of that?

And we don't know yet what's going to happen. But fortunately, there's a very large clinical trial. These are the human tests that are done to prove out the safety and efficacy of a drug that's going on right now. And we might have results by early 2026 that show one way or another whether they can have a beneficial effect on Alzheimer's disease. That's one example. There's two others I want to briefly mention, which I think people should...

definitely take some hope in. One is there's something called the infection hypothesis of Alzheimer's. And this involves the idea that certain viral infections, even something like herpes, which people may recall causes things like cold sores that resolve.

But those viruses may just hang out in certain organs of the body for even up to decades. And one of those organs is the brain. So there are people who think that if we aggressively treat that, there's a chance that we could see benefits for people who have Alzheimer's disease with the idea that it may be influencing the development. There's some kind of post-viral syndrome aspect to it. Exactly right. And then the third thing I wanted to...

really leave people with this message that we have agency in our lives associated even with Alzheimer's disease. There is no cure. There is no

surefire preventive approach to Alzheimer's disease. I am not an expert on all the claims about supplements and brain games and all that stuff, but all the experts with whom I've spoken don't believe that those are a way of for sure of preventing yourself from getting Alzheimer's or curing the disease. But what I do know is that certain things like high blood pressure, high cholesterol levels,

Maybe a diet that is not a healthful diet, lack of exercise. These are all things that could contribute to either the time in which people start to get Alzheimer's or the rate of severity of symptoms coming to the fore. And so what I would just say is people should understand that they can improve.

be someone who takes care of themselves. It'll pay dividends, not just for the possibility of forestalling the worst of Alzheimer's if you're unfortunately someone who gets that disease, but also just in your life as a whole. Yeah.

Now let's return to the depressing stuff, Charles. Patrick writes in to say, Medivation was a company in San Francisco that had a drug, Dimobon, with very strong phase two human clinical data for treating Alzheimer's. The preclinical and early human clinical data led to a half billion dollar deal with Pfizer. A lot of people got rich off this deal. It was only after phase three human data showed no effect whatsoever.

By this time, many people had cashed in, not to say this data was fake, but the value increase in an asset will allow many people to cash in before efficacy is known. This speaks to, I think, one of the incentive landscape for this world is such that it's not like you have to get the drug all the way to the end because people are willing to bet on the promise of a drug in such a way that...

You could make an enormous fortune with a drug that ultimately goes nowhere. At least somebody can make an enormous fortune even if a drug never actually reaches people to help them.

Yeah, it's extremely common, I'm afraid, even in circumstances where there's strong evidence of apparently fraudulent or apparently doctored data associated with a drug in development. The markets being what they are, the desperation to find something beneficial or effective in treating Alzheimer's being what it is, means that there's just enormous amounts of money that are sloshing around in the system. And people who are

these drug developers often get quite rich, even if their drug proves to be ineffective. A couple of kind of related comments here from listeners. Andrew writes, one of the foundation stones supporting the scientific method is the reproducibility of results of any given experiment. I've often wondered in this era of rapid technological advancement and the expense, complexity, et cetera, of experiments undertaken today, who is going to reproduce an experiment? What incentive would a person or organization have to undertake this experiment?

Martina relatedly writes, I've read that a lot of journals aren't interested in publishing studies that focus on replicating results. But that's supposed to be the entire point of publishing a scientific paper with a method section so it can be replicated. How should journals change their approach so they don't publish false results or give more space to studies that try to replicate things?

The replication crisis. Those are excellent questions. And it's well known that not just in Alzheimer's, but in many fields of science, there just isn't enough of that work going on. And part of it is that really replicating someone else's experiment is a surefire way to sort of sideline your own career. One is that it's hard to get that published in journals, as the listener has pointed out. And second is that for...

Young investigators in particular, to take that on and to potentially challenge others in your field, particularly if they're powerful people who have had results that cry out for replication because they're important results that are influential. To do that is to risk your career because you can be seen as someone who's a malcontent or someone who's not doing their own original work or someone who's complaining about the power structures of the industry. Right.

Well, and people have personal relationships too. I mean, the kind of key whistleblower figure in your book eventually finds doctored images and his mentor and close friends work and has to confront him about it. These are hard things. A user on Discord actually brings up something very related.

As a grad student in an elite lab 20 years ago, I discovered a colleague fabricated key results for a publication in addition to multiple other dishonest behaviors. I brought the results to a group meeting and left it for the private investigator. In the end, nothing was done, and the dishonest colleague has gone on to a career as a professor at Top 5 Programs.

There was not sufficient fear of negative consequences for the investigator in looking the other way. In fact, incentives were to not raise a stir. Is there now a formal process for students to follow if they suspect an issue? I think Rodney Milpitas, I think, has a similar query here. Rodney?

Yes, my question is that when you have a highly, you know, high-profile doctor who's documenting imaging, things are just blatantly false. There's people that work, you were just talking about, there's people that work under him, they see this every day, okay, and they should be blowing whistles.

Okay. And I understand it's easy to say, and it's extremely, because if you're close to that person, you've been, you know, that person a long time, but still the right thing to do is the right thing to do. Cause you can't imagine who it's affecting, how many millions of people that it's affecting. Okay. They have,

chronic problems and they're depending on these doctors and this information that is you know hopefully that even their mind even if it's not really working a lot sometimes it's what's in their mind that helps them think it's working and if that's what it takes to feel better sometimes so be it hey rodney appreciate your uh your position on that i mean

This is tough, though, right? I mean, whistleblowers know they're torching their career. They can be. It's very, very common. But I would just say that there's also an incentive, perverse incentive structure going on here to avoid confronting these kinds of issues. And when you look at how the process works, normally when there are allegations of image doctoring or other kinds of misconduct, it goes to the institution that employs that particular scientist.

This is the institution that has the most to lose and the least to gain from a robust, rapid, and well-conducted investigation, the results of which are ultimately made public. And so I would say, first of all, that we need to have...

a disinterested element to this investigative process so that there are fewer conflicts in looking at possible misconduct. I think the listeners are right. This is a big issue. I would say have some sympathy for the junior scientists in the lab, though, who see misconduct. Their careers often depend on the scholar whose work they would be criticizing. And

People aren't really that eager to torch their careers. And given the institutional weakness that you've described, they may not be protected by the institution. In fact, they may be punished for. Often that is the case. Do you think this problem as a result of these investigations, as a result of sort of like increasing pressure from inside the scientific research community itself, I think it's going to get better or worse over these coming years?

I actually have a great deal of hope that things are going to improve, partly because of the rise of the so-called image sleuths who have, in essence, forced the hand of some other institutions to start taking this stuff seriously. And I don't think they're taking it seriously enough yet. But I think that time is coming because...

Really, there's nowhere to hide anymore. People are all over these papers. They're all over the apparently doctored images in these papers. And so there is some pressure to do better. And so I feel it's inevitable that there will be improvement in this over time.

We've been talking with Charles Piller, investigative journalist with Science Magazine. You can continue to follow his work there, where I'm sure you'll continue following up on this. His new book is called Doctored, Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's. Thank you so much for joining us this morning, Charles. Thank you for having me, Alexis.

Thank you to all of our callers and commenters. Really appreciate your perspective on this difficult subject. I'm Alexis Madrigal. Stay tuned for another hour of Forum Ahead with Mina Kim.

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