Billions of dollars have been spent on researching Alzheimer’s disease, which afflicts more than six million Americans and is the fifth-leading cause of death among the nation’s elderly. Yet there is no cure, and the few treatments available show only modest evidence of slowing cognitive decline.
Fraudulent science may have steered the field in the wrong direction for decades, according to Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s, which was published Tuesday.
Charles Piller, an investigative journalist at Science, chronicles how the field coalesced around a central explanation for what causes the disease: biological chain reactions set off by clumps of amyloid-beta proteins. These sticky plaques have been found between the brain cells of deceased patients with Alzheimer’s since the disease was coined in the early 20th century. From the 1990s onwards, the “amyloid hypothesis” virtually crowded out all others, even though drug after drug failed to improve cognition while successfully clearing plaques from the brain. Doctored presents evidence that this hypothesis was reinforced by hundreds of important Alzheimer’s papers — led by star researchers, published in leading journals, financed by federal grants — that relied on falsified data.
In late 2021, Piller came into contact with the scientist who would eventually blow the whistle. Matthew S. Schrag, a young, untenured neuroscientist at Vanderbilt University, was finding alarming numbers of seemingly manipulated images in papers key to his field. Some offered support for an experimental treatment called simufilam, which has since flamed out. It was developed in part by a scientist at the City University of New York who’s been indicted for allegedly falsifying data to obtain $16 million in grants from the National Institutes of Health.
Then there was a landmark 2006 Nature study out of the University of Minnesota, which was widely received as affirmation of the amyloid hypothesis. Last year, it became one of the most-cited studies ever to be retracted. (The senior author acknowledged that the paper contained doctored images.)
In a Q&A with The Chronicle, Piller says that the questions raised by Schrag, along with an army of volunteer data sleuths, should serve as a wake-up call to the scientific enterprise. This interview has been edited for clarity and brevity.
What are the consequences for patients with Alzheimer’s that we may have spent decades barking up the wrong tree?
No one really knows for sure what would have happened had there been much more attention paid to alternative hypotheses. But clearly, we haven’t made progress, and it’s devastating for patients and their families and caregivers. I think it’s possible that we would have seen more progress in the disease had there not been this kind of scientific monoculture, you might say, in devotion to this one way of looking at it. Even though drug development is diverse, when you look at where the big money is going, most of it’s going into anti-amyloid work.
Your book makes the case that some of the blame for this phenomenon lies with universities. What are the incentives that make them in general so inclined to protect their own?
Typically, what happens when concerns about misconduct associated with research occur is that usually it’s NIH-funded, because that’s the major funder of biomedical research in the United States, and so the person who’s concerned about it would report it to the NIH. They would hand it over to the Office of Research Integrity, which is a separate agency within [the Department of Health and Human Services], and then ORI, 99.8 percent of the time, hands it back to the home institution of the researcher who might have been accused of potential misconduct, and it’s up to that university to look into it. These are institutions with the most to lose and the least to gain from a robust, prompt, and publicly accessible look at the possibility that their professors have been engaging in misconduct.
A kind of groupthink took over the bulk of the research community in Alzheimer’s disease.
So what you see is time after time after time that universities take months or even years to do their investigations, and then no one ever finds out about it. Some of the really egregious ones do come to light, but usually it’s because the universities have been dragging their feet for so long that it’s not done in a timely way. And the consequences can also often be very minor for the professors, even if they are found to have engaged in misconduct.
You write about how the amyloid hypothesis was so dominant that scholars were encouraged to insert amyloid language into their NIH-funding proposals; otherwise they wouldn’t get funding. Why did the NIH keep granting money to these projects even when so many people were struggling to replicate the finding that this protein buildup causes Alzheimer’s?
A kind of groupthink took over the bulk of the research community in Alzheimer’s disease. When this idea became so dominant, it became sort of assumed that this was the path that the community of researchers had to go down to be successful. And when an idea like that is so well-accepted, being a renegade, posing an alternative, ended up being met with great skepticism — because there were such sunk costs into it, both by the funders like NIH but also by the drug companies, and because eminent scientists had built their own careers around this hypothesis. The idea of it being wrong or being only partially right — or only being right in a tangential way, which is what some of the concerns are — was basically a bridge too far for NIH, and they therefore continue to fund this at a very, very high level.
Are there lessons that could be applied to other fields? How does a phenomenon like that happen, and what can be done to try to prevent such groupthink, in general, going forward?
Let me tell you why I think Alzheimer’s is unique in this regard. I’m not saying that there aren’t a lot of dead ends in studying other diseases. But when you look at the major killers — heart disease, chronic diseases like diabetes, cancer — these are diseases that have seen tremendous gains in medical science in recent decades, and part of it is that there are many tacks that have been taken on them. There have been drugs, radiation, healthy lifestyle changes, and a myriad of other things, even genetic treatments, that have this multifaceted approach looking at the diversity of these diseases and how best to examine it.
Alzheimer’s has been different for a few reasons. It’s a really, really hard disease to approach because the brain is so complex and so difficult to treat. So I don’t want to overlook the idea that this is just a really tough problem, and you can’t blame scientists for struggling with it. The second problem with Alzheimer’s disease has been that, because the amyloid hypothesis has been believed to be sacrosanct, it’s crowded out other ways of looking at it, so there hasn’t been the same multiplicity of approaches and ideas as you’ve seen with other diseases.
For a large chunk of the first half of the book, Schrag is struggling with whether to go public with his concerns about all this research. What about academe makes potential whistleblowers like Schrag hesitant to speak up about questionable research?
Powerful institutions don’t like to be questioned when reputations, money, grants, and the prestige associated with that is called into question by apparent misconduct. It can be a horrific problem for a university that they want to try to avoid, and so they often will do whatever they can to prevent these whistleblowers from having their misdeeds that may have taken place in universities come to light.
With Matthew Schrag’s own situation, I’m happy to say that he recently got tenure. It’s a great relief — a great relief for me, too, I might say. But when he was coming forward publicly, one of the big questions for him in our many discussions together was whether to go public. Of course, as a journalist, I really wanted him to. I knew that this story that was based on his exploration, and telling his personal story and the journey he took, was going to be critical to engaging the reader and understanding what this was about and to understanding that there was a dramatic element to it that we should all pay attention to. The struggle for him was that he was a junior professor just getting his lab really well-established. He had not yet gotten his first R01 grant from NIH. This is the pivotal moment in a young scientist’s career of getting a grant that has potential multiyear funding to keep the lights on in his lab, and he hadn’t gotten that. He was also in a situation where he was preparing himself to go after, in a public way, the leading journals in his field, some of the leading scientists in his specific area of research, and universities, and questioning the judgment of the NIH, his potential funder. When you’re going after all of the big institutional authorities that you depend on for your career advancement, that’s a pretty scary prospect.
Your book chronicles how a lot of data sleuths publicly brought to light valid concerns about Alzheimer’s research on their blogs or on PubPeer [an online forum for commenting on research]. A fair number of researchers on the receiving end feel that PubPeer is ripe for misuse and abuse. So I’m curious about your view on the internet in the data-sleuthing age: Do you think it’s a net useful tool for bringing to light misconduct, or do you think it creates more trouble than it’s worth?
I think it’s been net useful, no question about it. That said, I think we should be clear about why it has to exist now and possibly why it may become less necessary in the future. So why it has to exist is that, basically, the funders and the journals have been complacent, and they have failed to address this serious problem for many years. This kind of arrogant complacency, this position that they’re somehow above this and don’t need to worry about it, and this idea that “our colleagues wouldn’t do this and we’re just going to trust them,” has been shown to be absurd by this army of mostly anonymous people who have been flagging improper images in scholarly work for the last few years.
So what I hope, and what I think, is essential for the scientific community is for the journals and the funders to get smarter and more sophisticated about what they owe to the public and what they owe to the advancement of science that isn’t polluted with bad research. What that means is getting sophisticated in their use of AI tools to examine scientific images that come across their desks in these submitted papers or grant applications, and then also hiring experts who have the skill to assess the findings of these AI tools so they can go into it with a way of doing quality control that would ultimately obviate the need for people on the outside to, after the fact, show all the mistakes that were made.
Is there one big lesson you hope academics and academic institutions will take away from your reporting?
The scientific community needs to step away from the sort of arrogance where they think they know better than anyone, and to show some humility in thinking through approaches to Alzheimer’s and to the integrity of scientific work. And that’s going to require them to take a good hard look in the mirror.
