Ep. 468 The Alzheimer’s Research Crisis with Charles Piller

Team Cynthia
10 hours ago
34 min read

Today, I am thrilled to connect with Charles Piller, an award-winning investigative journalist for Science magazine whose work has also appeared in The Los Angeles Times, The New York Times, The Sacramento Bee, and other major publications. Charles is the author of Doctored, and he has been honored with several national journalism awards.

In our fascinating conversation, we dive into the trajectory of Alzheimer’s from its early framing as a diagnosis to its modern-day research landscape. We explore the concept of publish or perish within academic research, and we examine the dominant amyloid hypothesis, the forces shaping scientific narratives, and the role of institutions like the FDA, NIH, and research publishing in influencing research priorities. Charles shares his insights on the impact of falsified data and the broader implications for scientific integrity of the doctored images published in Nature in 2006. We also tackle the importance of lifestyle and risk factor modification in preventing neurocognitive decline.

You will not want to miss this compelling conversation with Charles Piller. His book is a gripping must-read on the fraud, arrogance, and tragedy in the quest to cure Alzheimer’s.

IN THIS EPISODE, YOU WILL LEARN:

How Alzheimer’s impacts our society and affects the caregivers of those with Alzheimer’s
Charles gives a historical overview of Alzheimer's
Some typical symptoms of Alzheimer's
How the amyloid cascade hypothesis led to the development of drugs that removed amyloid from the brain but failed to halt or reverse dementia
How doctored images can support experimental hypotheses and influence research
Charles highlights the need for more accountability within the scientific field.
How pressure to publish and perverse incentives have influenced Alzheimer’s research
Why ethical concerns matter when developing potentially hazardous drugs with limited benefits
Charles shares the potential benefits of GLP-1s for cognitive decline.
Why a multi-factorial approach to understanding and treating Alzheimer's is essential
Charles highlights the importance of self-criticism and humility within the scientific community.

“Millions of women are caregivers for people living with Alzheimer's, and it's a gigantic family burden as well.”

-Charles Piller

Connect with Cynthia Thurlow

Follow on Twitter
Instagram
LinkedIn
Check out Cynthia’s website
Submit your questions to support@cynthiathurlow.com

Connect with Charles Piller

On his website

Transcript:

Cynthia Thurlow: [00:00:01] Welcome to Everyday Wellness Podcast. I'm your host, Nurse Practitioner Cynthia Thurlow. This podcast is designed to educate, empower and inspire you to achieve your health and wellness goals. My goal and intent is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives.

[00:00:29] Today, I had the honor of connecting with Charles Piller. He's an investigative journalist for Science Magazine whose work has appeared in The LA Times, The New York Times, The Sacramento Bee, and other publications. He's also been honored with many national journalism awards and is the author of Doctored.

[00:00:47] Today, we spoke at length about Alzheimer's and the impact of the initial timeline of the trajectory of Alzheimer's both as a diagnosis and coming into modern days and the amyloid hypothesis, why scientific integrity is important? How the dominant paradigm of Alzheimer's developed from and is influenced by the FDA, the NIH journals and academics, the concept of publish or perish in academic research, how the Alzheimer's dilemma has led to desperation and choices that have in some circumstances led to poor quality research that's been doctored, how a Sentinel paper from 2006 in Natured had tremendous implications on Alzheimer's research due to doctored images, the role of falsification of data and misconduct, the impact of science infrastructure and how it can lead to fraud, data manipulation, and sleuthing, as well as cognitive dissonance and alternative ideas for the etiology of Alzheimer's and lastly, the importance of the role of lifestyle and risk factor modification for development of neurocognitive disorders.

[00:02:02] This is truly an insightful and valuable conversation. Charles' book is one that I thoroughly enjoyed. I know many of you will as well. It’s Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s.

[00:02:17] Well Charles, so such a pleasure to connect with you. I really enjoyed reading your book and I think it'll be of particular interest to my listeners because neurocognitive disorders, Alzheimer's are a concern of probably every aging woman, certainly the people and the patients that I interact with.

Charles Piller: Indeed, it's a society wide problem. And also, it's important to remember that there are millions of women who are caregivers for people who are living with Alzheimer's and it's a gigantic family burden as well.

Cynthia Thurlow: [00:02:48] Yeah, last year my father passed away and my brother and I were taking care of my stepmother who had end-stage Alzheimer's. And what was interesting to me is being privy to the Alzheimer's care, she was in an incredible facility but 95% of the people that were there, 10 people in this unit were all women. There was one male and it was interested interacting with the clinicians and experts that worked with the patients. And they would say, “It is largely-- At least from our perspective, largely a women related disease,” because women tend to live a bit longer. It's like if you live long enough, you're certainly at greater likelihood of developing neurocognitive decline.

Charles Piller: [00:03:28] Yeah, there's no question about that. My own mother, who died a few years ago, died with Alzheimer's. And I'm keenly aware of the kind of struggles that families go through, particularly with moms and grandmothers.

Cynthia Thurlow: [00:03:42] Yeah, absolutely. So, to give listeners some context, let's talk about, you know, 1974, the National Institute of Aging mentions here that Alzheimer's is the primary cause of dementia. And so from that point there's been this working hypothesis around what is driving, escalating rates of Alzheimer's. And I know that we'll get into the research and some of the fraudulent research that has been brought to light, but let's give us some context of what the last 40 to 50 years have been like in terms of looking at Alzheimer's from a perspective of better understanding, where it stems from and research dollars that are being supported to determine what's going on.

Charles Piller: [00:04:26] Sure. So actually, if you don't mind, Cynthia, let me just very briefly bring us back to the very beginning, you might say, when the disease was first characterized, and this was back in 1906 by the namesake of the disease, a German scientist, Alzheimer. And he was treating a patient who had very serious dementia symptoms. And after she died, he also was a pathologist and he examined her brain tissue and he found the characteristic signs of what we've been described as the characteristic signs of Alzheimer's disease. These are the so-called amyloid plaques, sticky plaques, and the Tau tangles. So, plaques and tangles, the tangles are kind of-- Look a bit like tangled string within nerve cells within the neurons of the brain. And the plaques are outside the neurons and they can accumulate and become patches on the inside the brain.

[00:05:30] And what Alzheimer's did is he said, “This is a new disease that's characterized by these three characteristics, plaques, tangles and dementia.” And the neuroscience experts and the neurologists of the time thought, very interesting, we'll keep our eyes on it. But for simple demographic reasons, it really wasn't much of a societal problem because there just weren't that many people living to the ages of the 70s, 80s, 90s, where the symptoms of Alzheimer's are much more prevalent.

[00:06:06] And consequently, it wasn't until the 1950s and 1960s and 1970s when the advent of really effective vaccines, antibiotics, treatments for heart disease, cancer, diabetes, all of these important medical advances greatly extended lifespans. And as a result, suddenly the population of older people was burgeoning, and many, many more people were coming down with the symptoms of dementia.

[00:06:35] And so now I'm back finally up to the genesis of your question, which is the 1970s, 1980s, when people started to study this intensively and a lot of government money started to be poured into understanding how to manage the growing dementia issues among older people. And it was actually for a long time, it was really beginning to be understood that amyloid plaques might play an important role in this process because they were found so often in the brain tissue of deceased Alzheimer's patients. There're contradictions to that idea, too, which we can get into later.

[00:07:15] But let me just say briefly that a hypothesis was developed that became very, very influential in the field, something called the “amyloid cascade hypothesis.” And it's pretty simple to understand. It says that the accumulation of amyloid proteins in the brain leads to a cascade of biochemical effects that eventually causes cell death and dementia symptoms. And this was an elegant, pretty simple, and straightforward way of understanding the progression of the disease that really captured the imagination of the medical and scientific communities and became the dominant way of looking at Alzheimer's disease.

[00:08:00] Okay, so that was in the early 1990s. So then there was a period of intensive drug development. So, the way in which doctors and medical scientists and drug companies all thought was the best way to approach this was to develop drugs that would essentially flush the amyloid proteins out of the brain, so that if these were the cause of Alzheimer's, if these were resulting in cell death and dementia symptoms, it's logical to think that their removal would either arrest or reverse the symptoms of Alzheimer's disease. And what happened is that a bunch of different drugs were developed and tested in people over a period of, I'd say, more than 10 years. And by the early 2000s, there was a lot of discouragement leaking into medical science about these drugs, because while they were becoming very effective in removing amyloid from the brain, they were very ineffective at halting or reversing the dementia symptoms. That was the whole point of the process.

[00:09:09] And in addition, some of these drugs were becoming quite dangerous. They could result in side effects that could at times even be deadly. And consequently, there was a bit of discouragement that had leaked into the entire biomedical field associated with Alzheimer's disease. So that's where we get to sort of, in a way, the genesis of what was kind of the trigger for me writing my book, Doctored. I could get into that story now, if you think it's the right timing for it.

Cynthia Thurlow: [00:09:40] No, I think it would be great because, again, it gives some context to this kind of burgeoning process and this focus on amyloid as being the primary driver of Alzheimer's.

Charles Piller: [00:09:50] Indeed. So, the way I started to become interested in this is that I became connected through mutual contacts with a scientist at Vanderbilt University in Nashville, a guy by the name of Matthew Schrag, young guy, getting his lab started, creative, interesting, thoughtful guy, also deeply concerned about scientific integrity because he knew that as he was treating his own Alzheimer's patients, because he was both a physician and is also a PhD scientist studying Alzheimer's disease in his lab.

[00:10:30] He knew that if this conduct affects the type of research that's done or the meaningfulness of it, or the validity of research, that it could have real effects on how patients are treated and how drugs are developed. And that's critical to him as a practicing physician. And so, he became very skilled at looking at scientific images, not just to understand what they meant in Alzheimer's studies, but also to understand whether they perhaps had been inappropriately altered. In other words, doctored in ways that would change their meaning. And in the process of doing this, he was involved in a long series of controversies of images associated with a particular Alzheimer's drug called Simufilam from a company called Cassava Sciences. And that's kind of a long story. I'm happy to go into it, but I'm going to skip ahead for just a minute.

[00:11:28] That drug, by the way, failed in its trials, and it was the source of numerous scandals and issues of misconduct that part of the story I tell in my book. But I think in a way, much more important to the overall story of Alzheimer's disease was his stumbling on a seminal study that was done in 2006 by doctors at the lab at the University of Minnesota, led by an illustrious scientist by the name of Karen Ashe, who had made quite a few contributions to the field, and her protege, Sylvain Lesné, is a French scientist who was working as a postdoctoral fellow for her at that time. And this study was important because it came at this moment of discouragement, when people in the biomedical sciences were thinking, “Mm. Maybe we're treading down the wrong path here, because we're not seeing the improvement we hoped for from these anti-amyloid drugs. And we are seeing potentially dangerous side effects.”

[00:12:37] So, what they did was a very clever experiment. They had the idea that one specific type of amyloid protein, which occur on a spectrum based on their, what's called “the molecular weight of the proteins.” And so, they thought one particular type, based on some of their lab testing, might be the key element of Alzheimer's disease. And they named it “Aβ∗56”, their star protein, you might say. And the 56 refers to its molecular weight, kind of a heavyweight among these proteins. And what they did is they used genetically engineered mice that produced copious amounts of human amyloids within their brains. Then they extracted this and purified it out to have just the ∗56 protein, injected that into rats, and the rats pretty quickly developed what were described as memory loss symptoms akin to the memory loss we see among Alzheimer's patients. And so, what was so interesting about this experiment was that it was for the first time an experiment that showed an apparent cause and effect, direct relationship between a particular substance, an amyloid protein, and dementia.

[00:14:01] Now, of course, animal experiment, not people, but of course, such an experiment wouldn't be ethical to do in people, so, animal experiments are important in this regard. And what was so interesting about it was that it really seized the imagination of the field. It reinvigorated the belief, the firm belief, that the amyloid hypothesis was indeed the true way to examine this disease. But maybe we hadn't been looking at the right type of amyloid protein or we hadn't been taking the right specific approach for a drug that would attack that protein. And so, this resulted in literally billions of dollars of new funding for a specific slant on the amyloid hypothesis involving this kind of heavyweight type of protein called “oligomer amyloid proteins,” and that refers to proteins that are soluble in the fluid that bathes the brain, rather than the sticky plaques that form these kinds of rigid formations within the brain.

[00:15:10] So, the idea was that the plaques might themselves be a problem, but these soluble forms of amyloid were also a serious problem. And so over a period of years, just literally billions of dollars from the National Institutes of Health was spent on grants for this type of research and billions of dollars in drug development costs for anti-amyloid drugs from the drug companies. And so that got us up to this period in the late teens and early 20s, where we really are at the cusp of drugs that finally made it to market. And that was a critical juncture as well.

Cynthia Thurlow: [00:15:52] Just to give listeners some perspective, the NIH is the largest biomedical researcher funder in the world, at least at the time of this book was written. And 10% of that research money goes into Alzheimer's research. So, to give you a sense of the scope of-- I think it was $37 billion in grants were awarded in 2022. So, to give you an idea, like how much money is being invested to try to determine what is the primary etiology of why Alzheimer's is developed. And so, what I found really interesting that stood out to me is this tremendous conflict of interest that's ongoing between the FDA, the NIH, corporate interests, influencing not only policies but also decisions. But the seminal paper that was done in 2006, kind of being the primary driver for pushing that amyloid hypothesis in lieu of other what I would describe as “emerging potential ideologies.” And you do touch on some of these. Can we talk a little bit about some of the things that were really-- I don't want to use the word suppress, but maybe that is the right way to describe it. Some of the other potential ideologies that were being brought up, but the research dollars weren't being invested into investigating anything beyond the amyloid hypothesis.

Charles Piller: [00:17:08] Yeah, sure, I'm happy to do that. Let me just say, contextually, science is vast. And when you're spending billions of dollars literally of federal funds on Alzheimer's research, it wasn't that they were just funding amyloid research. There were other things funded.

[00:17:24] I think the issue that you're referring to, which is an extremely important one and one that I describe in detail in my book, is that when there is a very dominant way of looking at a disease, when the institutional authorities of science, and by that I mean the primary funder, NIH, the regulator, FDA, the scholarly journals that are the gatekeepers of knowledge, and the universities that are the sponsors of all of this important work, when all four of those important institutional entities are working, in a sense, in lockstep in supporting this dominant way of looking at the disease, notwithstanding some other studies that are still being done to a far lesser degree of emphasis, then what you have is a situation where ideas can be crowded out, they can be starved for funding, and because an idea can be quite dominant, if you have illustrious important figures in the field who are completely convinced that that is the way to go, then it can be hazardous to one's career as a young scientist to propose alternate methods of looking at this problem and to have their innovative ideas well supported. Now, it doesn't mean they were completely crowded out. It just means that it gets harder, a lot harder. And the progress on those ways of looking at Alzheimer's was much slower than it was for the amyloid approach.

Cynthia Thurlow: [00:18:53] It's interesting and quite frankly, humbling as a clinician to understand all these little nuances that go on. And you're right that there's tremendous pressure. It's the publish or perish is the mindset. I had plenty of friends that were getting PhDs when I was training, and the amount of pressure on them to get things published and to be relevant to whatever area of medicine or research they were working within was, I mean, unbelievably challenging. And for many of them, they ended up leaving traditional basic science research to go to what I would refer to as probably better paying, maybe not as prestigious environments in the private sector, because it took a bit of pressure off of them.

Charles Piller: [00:19:42] Sure, that's a very important point. I think we can talk about this maybe more in a bit after we get into some of the concerns about Alzheimer's research that emerged in the course of my research for the book. But one thing that I think is important to keep in mind that you're already describing is there are some perverse incentives in academic science, and one of them is indeed the publish or perish issue, because young scientists are in a very competitive situation. It's so difficult to get that big grant that can get you on your way to fund your lab and to keep you going for a couple years so you can explore your ideas.

[00:20:20] And if you're being steered away from ideas that for which there is less funding and less support and less encouragement from the senior scientists, then of course, you're trying to do something that you can do to keep the lights on in your lab and to keep your assistants employed, etc. So that perverse incentive associated with the selection of research is one thing. It also encourages people to try to sometimes even cut corners. And again, we can talk about that later.

Cynthia Thurlow: [00:20:52] Yeah, I think that for me, again, as a clinician, not as a researcher, but certainly someone that, as I was reading the book, it calls into question that Alzheimer's research is one of probably many areas of research where, as you mentioned, cutting corners people that were sometimes, in some instances, which is incredibly tragic, we're manipulating data and manipulating information that then went on to develop drugs that were not only not effective, but in some instances, like some of the drugs that are newer to market, where people were developing hemorrhagic symptoms in the brain which were at times catastrophic. And so, I think about the beneficence first do no harm, which is something that all of us in medicine are introduced to that concept very early on. And I feel like in some ways, maybe with the pressure of trying to bring ideas to fruition, get funding, people sometimes forget their morals and obligations to basic science.

Charles Piller: [00:21:55] Yeah, I think there's a constellation of things that come together that make the Alzheimer's situation particularly tragic. And one of those is that for very understandable reasons, there's a lot of desperation in the community of people who are experiencing early cognitive decline and their loved ones. And that desperation leads people to make choices that are based on very limited options. And for some people, even a choice that has limited benefit, if any, and also has some potential very dangerous hazards associated with it is a choice they're willing to make.

[00:22:40] And personally, I don't criticize those choices. That's a personal choice people make with their family and physician. And it's understandable to me that some people would choose to do anything they can.

That said, you're absolutely right that it's tragic that those are the options that are being pursued most aggressively right now. Notwithstanding the many years of evidence that their benefits have been at best, disappointing.

Cynthia Thurlow: [00:23:09] Yeah, no, it's interesting to me. You do such a beautiful and objective job of bringing to fruition a wide range of fraud in Alzheimer's research. And you mentioned that this can sometimes be common or even the norm in Alzheimer's research in particular. Again, because I think of these pressures not only from patients desiring a favorable option for their loved ones, but also clinicians and researchers feeling like they're struggling to find something that works. That whole concept of, it's going to be this one paradigm that is going to resonate that they're going to be able to create drug opportunities or profiting from said drug opportunities.

Charles Piller: [00:23:52] Yeah, that's absolutely right. And, well, maybe this would be a good time to introduce the concern that Dr. Schrag at Vanderbilt found with this very important 2006 study. So just to be clear about what this study was, it was again, this one where they injected rats with this particular amyloid protein and described a so-called cause and effect relationship between the protein and symptoms that are similar to Alzheimer's.

[00:24:20] And what was so interesting was that he stumbled on this in a process of refining his own ability to see and understand potential misconduct in Alzheimer's studies. And he was examining this study, and he knew immediately how important it was, because it was a very important study in the field. It was published in the journal Nature, which is one of the two eminent general science journals in the world. I actually work for the other one, Science. They're kind of, I guess you could say competitors somewhat, but they're both very important journals. And when you get a paper published in one of them, then you know that the world's going to take notice of it.

[00:25:02] And secondly, it has been cited thousands of times in the scientific literature, one of the most cited basic science studies in Alzheimer's disease over the last few decades. And so that sort of impact has a big effect on the field. And what was-- I remember this moment very vividly. He and I were talking on the phone. We had literally dozens of conversations around this period of time, because we were working together to understand the situation that he was uncovering that I was beginning to write about.

[00:25:33] And we had a kind of a moment of stunned silence because with the realization that this important study he found was based on a series of apparently doctored images. Images that changed the scientific findings in a way that would tend to support the experimental hypothesis when the actual data didn't support that hypothesis.

[00:25:55] And when I say doctored, let me just explain briefly to give you a visual picture of it. So, what we're talking about as an example is that in a lot of these studies, you have something called micrographs, which are very, very much expanded views of small bits of brain tissue that show certain characteristic formations in the brain, often in a brain that has signs of Alzheimer's disease. And using a program like Photoshop, you can enhance certain features or fuzz out certain features or clone certain aspects of an image and place them in another location, all to accentuate an experimental hypothesis or decrease countervailing evidence in an image.

[00:26:43] There's also another kind of image that shows the amount and presence of certain proteins. Again, this is very important in Alzheimer's because what you're doing is looking at the availability of proteins and what their potential impact might be on a brain. And when you look at these proteins, they appear in something called a “Western blot,” as kind of series of irregularly shaped blobs. But they're very easily manipulated in digital tools to move them around or change their characteristics, make them lighter or darker, to do things that would, again, accentuate or diminish certain effects to support an experimental hypothesis.

[00:27:28] And when Dr. Schrag found lots of examples of this kind of stuff in this very important paper. Of course, we were both very stunned by it and had to take a moment to gather ourselves to understand what the implications might be. And those implications were that a whole generation, you might say, of Alzheimer's research that had been inspired to a significant degree not by this one study, but by this study and some others may would be called into question. And given that the history through that point is not one of success of developing drugs that arrested or reversed the symptoms of the disease, but the very best that could be done was to find drugs that showed signs of very minutely slowing the progression of Alzheimer's disease.

[00:28:22] In other words, patients would still be suffering from continuing worsening cognitive decline, but at a slightly slower rate, with the risk of potentially deadly side effects in the mix. So, you had this very unsatisfactory situation. And when Schrag found this evidence of image doctoring, it made me realize that I needed to look more deeply into this whole subject and to understand better whether this was a pattern of behavior within the field that could have a broader, bigger question about the way in which Alzheimer's research had been conducted, and what did that really mean going forward in the field? And that sort of got me on the path of looking at all of these matters very carefully and broadening my journalistic look at it to thousands of studies by many, many dozens of researchers, including some other very important people in the field.

Cynthia Thurlow: [00:29:25] As a Science writer, what was that like for you when you stumbled upon the realization that this is a significant breach in ethics and the implications are quite vast and broad? I would imagine it was probably terrifying to realize that the implications, maybe at the time, you may not have realized it, but as the book came together, the realization that a great deal of what we know about Alzheimer's disease stems from these kind of sentinel papers.

Charles Piller: [00:29:55] Yeah. So, I guess I could say it was-- Personally, the effects were multiple. I was humbling to see this, also a bit scary. And at the same time, of course, as an investigative reporter, this is what I do and what I live for, in a sense, is to find out potentially important information and to try to describe it in an understandable way to a large audience. And that was sort of my goal is to be able to have a beneficial effect on the thinking in the field, which was really what it was all about.

[00:30:30] I wanted to just take one step back, if I could, briefly, and just to say that my observation and studies that have been done about the falsification of data and information in research has shown over and over again that even though it's a big problem in Alzheimer's research, it's also present in virtually all scientific fields. And let's face it, in every walk of life. It's scientists, plumbers, lawyers, even journalists, I mean, there's always people who are willing to cut corners, even engage in corrupt methods in order to be self-serving or to benefit certain ideas. And the issue really is not that it's the predominant way of operating, I'd say it's just really just a tiny percentage of all physicians, of all scientists are engaging in appropriate doctoring of images or other kinds of misconduct.

[00:31:28] But strategically placed, placed in a position where it has influence, even this relatively small number of problematic studies can have wide ranging influence. It can steer ideas in a wrong direction. It can cause people to develop confidence in certain ways of looking at a problem that aren't based on solid evidence. And so why is it particularly a problem in Alzheimer's disease? Well, really, it's because even though you see the same sorts of problems crop up in research on heart disease or diabetes or cancer, it's very clear that these things do happen in those areas. Fortunately, we have really excellent developments in those diseases that have saved lives, that have increased lifespans, that are imperfect at times but have been very beneficial to people. Not so really for Alzheimer's disease. It's particularly tragic because there has never been a really good treatment that has had a significant effect of arresting or reversing the cognitive decline that is so tragic. And consequently, when you see these falsifications, when you see this kind of misconduct, it's particularly harmful and devastating to I think the research community and to patients as well.

Cynthia Thurlow: [00:32:58] There's an interesting quote in the book. It says “You can cheat to get a paper, a degree, get a grant, but you can't cheat to cure a disease. Biology doesn't care.” It was one of the quotes that I pulled out and I thought this sums up the book beautifully that this is this kind of prevailing message. There are no shortcuts.

Charles Piller: [00:33:17] No they're not. And I think it addresses something that's very important in science to understand. And you'll hear people saying this all the time, which is that “science is self-correcting.” And ultimately that's true for the reasons that you just said in that quote by Matthew Schrag. Science is self-correcting because if it doesn't work, it doesn’t work. But you have to understand that certain ideas, scientific ideas, once embedded in the scientific culture, once they gained prevalence and once an enormous amount of money and careers and reputations are staked on their veracity, even if they're wrong, it can take a very long time to reverse that incorrect thinking. And consequently, even though science will eventually self-correct, lots of harm can be done from incorrect ideas and their terrible effects for years and years.

Cynthia Thurlow: [00:34:13] It was interesting when I was reading the book, I think Karen Ashe’s interaction with you when her lab had been downsized and she was feeling probably in many ways like she perhaps was kind of processing what had gone on in terms of that Sentinel paper. And then the work that she had done with Sylvain Lesné and what it had led to. Did you feel like there was remorse or was there-- Did she fully understand the impact of that paper and the doctored information, or did you feel like she was not in a position to be able to accept some responsibility for what it transpired?

Charles Piller: [00:34:53] Yeah, that's a terrific question because it's-- For me, it was really quite a moving and difficult kind of experience as a reporter. I went and visited her in her lab for a couple days and I had been trying to get an interview with her for a couple of years, but she finally agreed to one, which I'm very grateful for. And I credit her with being willing to talk with me after I had already written-- This is before the book was published, but after I had already written articles that had been challenged her work in really significant ways and as you mentioned, resulted in her losing a lot of funding because the information in the articles that I wrote was not just incontrovertible, but it was believed by funders, other scientists, the scientific research community. That paper, by the way, was ultimately retracted.

[00:35:43] And so, the scene you're describing was one where I have to say that I had a lot of sympathy for her because I think the evidence that I've seen strongly suggests that her protege Sylvain Lesné, was at the heart of the problems associated with image doctoring. And now he denies this, but the evidence is very strong to suggest that he was involved in that. And, ultimately, he was forced out of the University of Minnesota. He resigned his post actually just a few months ago, and he was working for her, if you could say that she was responsible, it was really for being complacent about, under her roof, under her funding, permitting an egregious act, series of egregious acts of image doctoring that had very important and deleterious effects on the field.

[00:36:38] And so I would say that my experience of her was that she was in some denial about the whole thing, about the importance of it, and she blamed me for her downfall. And she invited me into her lab as a very devout religious person. She's a Christian and believes deeply, and kind of forgiving people from the religious perspective on that. So, the whole thing was a bit strange. Just to be clear, I don't see any contradiction between devout religious people and science. Many wonderful, amazing scientists over the years, including I might add, Matthew Schrag, find religious experiences and religious practice very important in their lives. And consequently, it wasn't the religious part of it that I found unusual. What was so strange was this sense that she said that she had forgiven me.

[00:37:31] And what was ironic is that it was, I think, part of her difficulty in facing the challenges and the problems that had come through her lab after spending years contributing greatly to understanding of basic science behind Alzheimer's, she had to face this very, very difficult moment in her career. And I guess for some reason she felt that she really needed to blame me instead of looking inward and understanding how those events had transpired.

Cynthia Thurlow: [00:38:01] Yeah. How her actions had contributed to what had transpired. I felt when I was reading that particular section, it was so clear to me that there was a lack of-- As incredibly smart and accomplished as she is, there was a lack of processing or understanding or inability to understand her contributions to what had transpired and how that had left her in a state of disgrace or lessened opportunities within academics because just to me it felt like she became very small. Like she suddenly went from being this acclaimed researcher to being in a position where her accomplishments were no longer what they had been before previously.

Charles Piller: [00:38:45] I think there's a lot of truth in that, Cynthia. And, maybe this would be a moment to say that. So, Karen Ashe, again, she's someone who is among many scientists who didn't personally doctor images, but were affected by it in their careers because of, I would say, a combination of the whole scientific infrastructure, the institutional authorities that I mentioned, the funders, the regulators, the universities, and the journals, showing a lot of complacency and inattention to the problem of data manipulation. And as a result, you have a lot of cases where people just kind of make assumptions that everything's fine when it's not fine, when there aren't enough eyes on it, and when the damaging effects of these things are too late to intervene before they become potentially very harmful to the field.

[00:39:42] And so, I wanted to mention that. So, the bigger story of the book and the bigger story of Alzheimer's research is that this case at the University of Minnesota in 2006 was one of literally hundreds and hundreds of important scientific papers that had been based on apparently doctored data, doctored images or improperly used images, where they would develop an image for one experiment and then paste it into a new experiment that had a different kind of set of circumstances, but because it could vividly show an example that would be helpful to that second study. Totally improper, scientifically, total misconduct, and yet unfortunately had been way more common than people understood.

[00:40:29] I should mention that for me, one of the most disastrous and telling examples of all this was a guy by the name of Eliezer Masliah, who was at the time I started investigating his case, was the neuroscience director at the National Institute on Aging. And he had a multibillion-dollar research budget every year to give grants and to do research in labs, even within the NIH itself. And Masliah, who had been an illustrious scientist prior to that job at the University of California in San Diego, he was one of the most eminent scholars in the field, one of the most influential scientists in both Alzheimer's and Parkinson's disease. He had published about 800 scholarly papers and was one of the most cited scholars in both of those fields, so this was no small fry. This was a big man with important work, important influence in the field, steering, helping to steer literally billions of dollars a year, lots and lots of it, most of it probably the largest share of it going to Alzheimer's research.

[00:41:40] And what I found with the expert work underlied this part of the book, the expert work of four forensic image sleuths, they call themselves. This would include Matthew Schrag, but also Mu Yang, who is a scientist at Columbia University. Kevin Patrick, who is a person who's a nonscientist, but an expert in examining scientific images digitally, he’s self-trained, but incredibly skilled and Elisabeth Bik, who's an illustrious, well-known expert in forensic image analysis. Those four teamed up not just on the Masliah Dossier as we call it, but many others to help me understand the depth of the problem within Alzheimer's research.

[00:42:24] But regarding Masliah, that team, led by primarily by the work of Mu Yang, found 132 papers of his that contained apparently doctored or misused images. That's a lot of papers. And when my story came, I actually did a story about this for Science prior to the book coming out because I felt it was unethical to hold that such an important person, such an important player. I couldn't hold it for a few more months until the book came out. So, the story ran in Science and he was pushed out of his post the same day the story came out. So that's the sort of impact that even the National Institutes of Health could not ignore. And they generally, unfortunately, have been pretty complacent about these matters.

[00:43:09] So what I'm trying to describe by giving you that story is that part of the problem is that the institutional authorities haven't taken this seriously enough. And when you have a combination of sunk costs into research and institutional prestige at risk and careers at risk for either having doctored data or being in a situation where your colleagues doctored data but it reflects poorly on you, or in a situation where you've been involved in drug development that was based in part on suspect information, all of these things create a lot of resistance to examining this situation clearly.

[00:43:55] I think some scientists, when some of my revelations about these issues came out, some scientists said that they this field needed to take a good hard look in the mirror and think about the process. And others have been very critical of me and the book. And I want to acknowledge that criticism, that these are people who disagree strongly and feel very much committed in particular to the benefits of pursuing the amyloid hypothesis as crucial to solving the problem of Alzheimer's disease.

[00:44:33] I want to say that in my opinion people should read the book if they're interested in the controversy. There're ways to find out about it. But read the book and draw your own conclusions and see that I have provided really detailed source notes. You can check my sources if you want, make up your own mind about the veracity of the findings of the book.

[00:44:54] But the point I'm trying to make here is that people who have been critical, these are-- some of them are people I respect greatly who have contributed to the field. I think, unfortunately, though, in a lot of cases they're not describing the book accurately. They're engaging in what are called “straw man arguments.” So, they're mischaracterizing the book and then criticizing the mischaracterization. And my view is that the field needs to examine these things closely, that the amyloid hypothesis and amyloid proteins are clearly related to Alzheimer's disease. And nothing in my book suggests otherwise. But what my book does suggest is that taking a more broad-minded look at the disease and being self-critical in understanding where things might have gotten off the rails and where the emphasis on one way of looking at the disease may have proved to be deleterious to understanding better how to cure Alzheimer's ultimately or at least arrest the symptoms. Those are things that I think the field needs to show a little bit more humility in the leading scientists really need to show that they can take those things to heart.

Cynthia Thurlow: [00:46:02] Yeah, I guess as an outsider looking in, having read the book and feeling like you did a really incredible job of being objective and conscientious and detail oriented is, and this is not unique to science, cognitive dissonance. This exists in every part of society that we live in. But when I look at-- And I'm one of those people like as I'm reading, I'm taking notes as I'm going, but just to give listeners some perspective, by 2006, 43+ drugs had failed to get FDA approval for this hypothesis. And I think that when you reflect on-- obviously if everyone is focused on just one hypothesis, and as you see astutely said, could amyloid be contributory? Sure. But there's probably some other etiologies, whether it's related to a virus, whether it's inflammatory. And I would probably make the argument that there's some degree of inflammation that is driving a lot of the cognitive changes. There's some piece of this paradigm that we haven't yet been able to fully appreciate and understand. There's probably people doing good work in this area right now. They're just not getting their work highlighted the way that this amyloid hypotheses labs had been in the past and certainly now.

Charles Piller: [00:47:20] Sure, that's a really good point, Cynthia, and I can speak to that directly. But I should just mention that, again, one of the problems is that when there are such sunk costs on pursuing this method of approaching Alzheimer's disease, there's just, it's enormously difficult to dislodge the emphasis from it.

[00:47:41] But let me just address the other alternative ideas specifically. So again, these are unproven and it means that they're being looked at. And I think it's important that these additional ideas be given enough time and attention to see whether they might be fruitful. This is the natural way in which scientific discovery has to proceed, but some of the ones that I'm very encouraged and interested in, one is the infection hypothesis of Alzheimer's disease, where possible, that latent viral infections might have a role to play or be important in the cognitive decline associated with Alzheimer's.

[00:48:22] Let me just give you an example, one is herpes virus, which listeners, I'm sure know can cause cold sores that eventually resolve. And people think, “Okay, thank goodness, I'm done with that.” But sometimes these viruses can hang out in organs of the body, including the brain, for up to decades and be latent in the sense that they're not causing any observable problem, but then might play a role in cognitive decline.

[00:48:53] And so, there are studies going on right now, clinical trials, which of course are experiments involving testing drugs with people. There are experiments going on right now to test whether treating herpes virus might result in a beneficial effect on early cognitive decline symptoms in Alzheimer's patients. And so, I'm looking closely at that one because I think it's fascinating and there's a lot of signs from the basic research that there might be a role that viral infections could play in the disease.

[00:49:24] Another one that I think is really interesting is the GLP-1 inhibitors. So, people of course know that these are the drugs that have maybe kind of become the wonder drugs of our time and have been suggested as being beneficial not just for obesity or diabetes, but possibly for all kinds of human ailments. And one of those is cognitive decline and associated with Alzheimer's. And so right now there's a very large clinical trial, Phase 3 trial. So, this is usually the last trial before the consideration of possible approval by FDA for marketing to the general population.

[00:50:06] There's a trial going on to see if these GLP-1 inhibitors might have a beneficial effect on early-stage cognitive decline. And so, to me, this is a drug that's already shown anecdotally to have possible evidence of benefit. So, I think what we're seeing here is opportunities to address things like viruses, like brain inflammation, elements of the disease that might either by themselves or in tandem with issues related to amyloid and tau proteins in the brain, could work together to cause the disease and might require, we might need a multifactorial approach to arresting the symptoms or reversing them.

[00:50:53] The other thing I wanted to mention, and I know that your audience is interested in this, it's that people should really remember that we have agency in our lives even when it comes to a terrible and terrifying disease like Alzheimer's disease, what I mean by that is that even though there's no cure for Alzheimer's disease, even though that I'm not an expert in this, but I'm not aware of any brain game or nutritional supplement or lifestyle change that will ultimately and reliably prevent Alzheimer's, what we do know is that there are risk factors that we have some control over. High blood pressure, high cholesterol, diets that are not nutritionally sound or well balanced, sedentary lifestyles, all of these things can contribute to either the earlier onset of Alzheimer's disease, if you're a person who's unfortunate to eventually get that disease, or the severity of the disease once you do get it. So, the chances of forestalling or lessening symptoms are there. If we remember that living our best lives, which is to take care of those risk factors, can pay all kinds of benefits, including the possibility having a beneficial effect, the possibility of Alzheimer's disease. So really remembering that agency we have, I think is very important.

Cynthia Thurlow: [00:52:25] No, I'm so glad you brought that up because lifestyle as medicine is so critically important. Sleep, stress management, nutrition, ensuring that we don't ultimately develop the diseases of lifestyle like high blood pressure and lipid disorders and diabetes, all of those things are important. We do have control over that. And I think that for many individuals, and certainly women, as they're transitioning from perimenopause to menopause, men go through andropause, it's not nearly as dramatic. There are hormonal reasons why we become more susceptible to diabetes and metabolic disease, that loss of estrogen and insulin sensitivity. And so, there are definitely things that we can be doing proactively.

[00:53:08] If there's someone that's impacted by Alzheimer's right now, do you feel like families and loved ones and clinicians should be hopeful about the progress on Alzheimer's, given some of the setbacks that we see that you beautifully outline in the book, I think about it from the perspective as someone who had a loved one that passed secondarily to Alzheimer's last year. As a clinician kind of looking at this, I keep looking at it differently the older I get, like, let's be honest. But if someone's listening, should they continue to be hopeful that we're going to get to a point where we will have drug therapies that can halt or slow the progression of this terrible disease?

Charles Piller: [00:53:51] Yeah. I feel optimistic, I do. I think people should understand that these things, there's no way to predict with any degree of certainty when dramatic developments will occur that really have a gigantic effect. The studies that I mentioned, for example, involving infections and GLP-1 inhibitors, I mention them because those are the sort of junctures where you might see a leap forward. And if you do, then the benefits might become something that people right now who are maybe in their 50s, 60s, 70s, who are thinking about these issues might be able to see something on the near-term horizon. I think that there's so much creative thought going into this that, yes, there will be something that comes through. Alzheimer's can be a multifactorial disorder disease, and we need people looking at all those factors.

[00:54:45] I wondered if I may, Cynthia, just mention something that is very disturbing to me now about what's going on in scientific research and that has to do with the attacks on universities and on research funding by the Trump administration. Now, I just want to say this has been a little bit strange for me because both RFK, Jr. and Jay Bhattacharya, who is the now the Director of the National Institutes of Health, both Trump appointees, mentioned my work in their congressional hearings associated with their appointments to those jobs. And look, I stand by my research. I stand by the importance of looking at these issues. I don't take a thing back about it.

[00:55:32] And I'm glad to say that the things they mentioned about my research were really spot on. They were describing concerns that an overemphasis one way of looking at the disease may be crowding out their ideas and other possible remedies associated with Alzheimer's. But what I want to say quite clearly is I think the slash and burn approach to research funding and to eliminating whole programs within universities and to defunding labs and big studies that have been very important and might still be very important is the wrong way to approach this, even if some of those studies are in areas that I think have unfortunately not been fruitful. I think it's really important that the scientific community take a good hard look in the mirror and be honest and less complacent about their activities. But that doesn't mean that the funding should be cut in a haphazard way. I think it's extremely harmful, and I disagree with it completely.

[00:56:34] I might add that as a citizen and at all of us as people who might be patients or who are taxpayers, we have the right and obligation to ask these institutional authorities to up their games to get better at what they do, to be able to detect misconduct within scientific research and to try to reverse the possible effects of that understanding of diseases. It's very important that we insist that they do better. But insisting that they do better doesn't mean pulling apart their institutional memory and cutting their funding to the point where they can't do their work effectively or eliminating whole programs. So, these things are not in conflict, but we need to be careful how we go about it.

Cynthia Thurlow: [00:57:20] No, I think you bring up excellent points. I mean that continuity is important. I have several friends whose children are entering into doctoral programs this fall, and several of them have been impacted-- Their funding has been impacted. And for listeners, if they're not aware that most doctoral positions, they're funded by a university or by a grant. And so withdrawing funding impacts not just existing research. It impacts young scientists and young people's opportunities to be able to look at some of these problems, not just Alzheimer's, but many other important issues. So, thank you for bringing that to listeners attention. Thank you for the book and the work that you do. I have so much respect and admiration for Science writers. You are the super sleuths and the work that you do is so necessary and needed. Please let listeners know how to connect with you outside of this podcast, how to get access to your books and learn more about your work.

Charles Piller: [00:58:19] Sure. And thank you so much, Cynthia. Listeners can always find out much more about the book and how to contact me at my website, which is charlespiller.com. And it's all up there. You can read reviews and see what other people are saying about the book. To find out more information and how to reach out to me via email or other methods.

Cynthia Thurlow: [00:58:40] Thank you so much for your time today.

Charles Piller: [00:58:41] And thank you Cynthia for your interest.

Cynthia Thurlow: [00:58:45] If you love this podcast episode, please leave a rating and review. Subscribe and tell a friend.

Tune in