671. Why Has There Been So Little Progress on Alzheimer’s Disease?

Summary

Freakonomics Radio Episode 671: Why Has There Been So Little Progress on Alzheimer’s Disease?

Original Air Date: April 17, 2026
Host: Stephen J. Dubner
Guests: Matthew Schrag (Vanderbilt University Medical Center), Charles Piller (Science Magazine), excerpts from several researchers and relevant institutional statements.

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Episode Overview

This episode seeks to unravel why, despite tens of billions of dollars in research, so little progress has been made in treating Alzheimer’s Disease. Host Stephen Dubner examines whether a dominant scientific theory—the amyloid cascade hypothesis—has stalled real advancement, and investigates allegations of manipulation and fraud that may have derailed the search for effective therapies. The episode features investigative journalist Charles Piller and neurologist/whistleblower Matthew Schrag, who expose deep problems at the intersection of science, medicine, academia, and regulatory bodies.

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Key Discussion Points and Insights

1. The State and Scope of Alzheimer’s Disease Research

• Alzheimer’s affects over 7 million Americans, mainly over 65, with no cure or highly effective treatment in sight ([01:02]).
• The disease was first documented in 1906 but, despite National Institutes of Health (NIH) spending ~$4 billion/year (second only to cancer), progress remains stymied ([01:02]–[02:32]).
• Alzheimer’s is increasingly seen as a disease of both environmental exposure and social inequality ([05:52]).
  • Pollution, obesity, and lower educational attainment are risk factors ([05:52]–[07:18]).

2. Dominance of the Amyloid Hypothesis—and Its Problems

• Since the 1990s, Alzheimer’s research has centered on the amyloid cascade hypothesis (accumulation of beta-amyloid plaques causes the disease) ([10:33]–[12:25]).
• The field’s heavy focus on amyloid has absorbed most funding, leaving alternative avenues under-explored ([12:37], [48:31]).
• Matthew Schrag (11:08): “Since about 1990...the main thought in this field is that the plaques, this little beta amyloid protein...is the primary driver of the disease. A huge amount of the effort related to drug development has been dedicated to preventing it from accumulating or breaking it up.”

3. Whistleblowing and Uncovering Research Misconduct

a. Cassava Sciences and Simufilam ([14:42]–[22:01])

• Schrag was hired to analyze alleged data manipulation for the drug Simufilam, developed by Cassava Sciences.
  • Found image manipulation in key scientific papers supporting the drug ([17:49]).
  • Schrag and whistleblowers took concerns to the FDA and NIH, but faced sluggish, opaque responses ([19:46]–[21:12]).
  • DOJ initially indicted scientist Haoyan Wang for data fabrication but later dropped charges; Cassava paid a $40 million SEC settlement and abandoned the drug ([32:10]).

b. The Lesné and Ashe 2006 Nature Paper ([24:34]–[31:28])

• A pivotal 2006 paper, cited thousands of times, used manipulated images to support the amyloid oligomer hypothesis.
  • Retraction finally occurred in 2025, after years of university stonewalling ([30:56]).
  • Co-author Karen Ashe claimed no prior knowledge of manipulation ([31:28]).

c. Systemic Research Irregularities: The Masliah Dossier ([33:49])

• Investigation found egregious image manipulation across 132 papers by Eliezer Masliah, who also ran the neuroscience division at the NIH’s National Institute on Aging ([33:49]–[36:25]).
• The NIH, when presented with evidence, waited until just as the exposé was published to announce Masliah was out of his director role ([36:35]–[37:33]).
  • Charles Piller: “You’re entrusting the organization that has the most to lose...with investigating possible misconduct. This is exactly the wrong approach.” ([29:29])

d. Reckoning with Personal Betrayal: Schrag and His Mentor ([39:30]–[46:31])

• Schrag discovers his undergraduate mentor, Othman Greeby, manipulated images in several co-authored papers, including Schrag’s earliest work ([39:30]–[43:09]).
  • Greeby admits to “polishing” images but denies outright fabrication ([41:54], [46:31]).
  • Schrag expresses deep personal pain but insists on upholding scientific integrity.
    • Schrag: “A lot of times people who have trouble in one domain can still have a lot of value to bring to the table... I told him that if he could find it in himself to speak out... that his role as a teacher could just be exponentially more important.” ([43:32])

4. Systemic Failures in Scientific Oversight and Regulatory Capture

• Academic and governmental self-investigation is fundamentally flawed ([29:29]) and often too slow to protect the integrity of science.
• The episode exposes “regulatory capture”—where FDA officials involved in drug approval move to lucrative industry jobs after approving questionable drugs ([48:31]–[49:08]).
  • Piller: “This drug [Aducanumab] was essentially the product of regulatory capture... Working hand in glove with the company that was promoting and trying to get the drug approved.” ([49:08])

5. The Narrow Focus’ Cost to Science and Patients

• Billions have been spent on anti-amyloid therapies, but treatments offer only minimal (often clinically insignificant) slowing of decline and carry real risks ([53:08]–[56:04]).
  • Piller: “They are dangerous. They can cause brain swelling and bleeding that has... resulted in death. Third, they're not effective in arresting the symptoms of the disease.” ([54:29])
• The “monoculture” of the amyloid hypothesis has stifled innovation by making funding for alternative hypotheses very difficult ([56:04], [59:14]).

6. A Way Forward—Expanding the Research Framework

• Schrag suggests refocusing Alzheimer’s as a waste clearance disorder, not just about amyloid or tau, integrating vascular health and other pathways ([56:11]–[57:59]).

  • Aggressive blood pressure control shows actual memory benefits—potential clues for broader strategies ([57:40]).
  • Need for research “renaissance” mirroring progress in stroke and epilepsy ([58:02]).
  • Diversity in research hypotheses should be encouraged.

• Memorable Quote (Matthew Schrag, 60:08):
  “One is that we need our memories to last a lifetime, to really get everything out of life that we're trying to get out of life.... A lot of the benefit of [medical] advances are being lost to this disease. If those extra years... are of poor quality, this is something that affects all fields and a huge number of people.... There must be something that we can do about it. This is one of the challenges for our generation, is to crack the code on this set of diseases, to make sure that the quality of life at the end of the life is what it should be.”

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Notable Quotes & Memorable Moments

• Charles Piller (02:32): “No one’s getting better with these drugs. Every scientist who works with them, every clinician will say the same. If they don’t, they’re lying.”
• Matthew Schrag (13:57): “I think I probably would [blow the whistle again], simply because of how I’m wired... But sometimes you need to make a decision and just go with it.”
• Matthew Schrag (18:29): “There's a difference between seeing something suspicious and being able to prove it. ... Not random things, not accidents or slips... but a coherent pattern.”
• Charles Piller (48:31): “Nearly all of them have built their careers on explaining, exploring, and expanding the benefits and the importance of the amyloid hypothesis. Their money, their prestige ... all tied up with that.”
• Charles Piller (51:54): “Trust must be earned.... We can be highly critical of attacks on science... and at the same time, we can insist that the institutional authorities of science ... do better at their jobs.”
• Matthew Schrag (62:02): “There's definitely been some degree of backlash, and I think that's expected and almost unavoidable. Some opportunities lost, but I think that's okay. There's also other opportunities gained.”

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Timestamps for Important Segments

• [01:02] – Introduction to Alzheimer’s, scale of the disease, and NIH funding.
• [05:52] – Environmental and socioeconomic contributors to risk.
• [10:33] – The amyloid/tau model and the dominance of the amyloid cascade hypothesis.
• [13:41] – Matthew Schrag’s dual role as researcher and whistleblower.
• [14:42] – Whistleblowing case: Cassava Sciences and Simufilam.
• [24:34] – 2006 Nature paper and image manipulation at University of Minnesota.
• [29:29] – Flaws in research oversight and university self-policing.
• [33:49] – Systemic problems: The Eliezer Masliah case at NIH.
• [39:30] – Matthew Schrag’s personal and professional reckoning with his mentor’s misconduct.
• [48:31] – “Cabal” of self-interested researchers, regulatory capture, and institutional conflict of interest.
• [53:08] – Effectiveness and cost of anti-amyloid drugs, and criticisms thereof.
• [56:11] – Rethinking Alzheimer’s as a “waste clearance” failure; blood vessel health as a target.

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Thematic Takeaway

The episode powerfully exposes how entrenched scientific dogma, conflicts of interest, and failures in oversight have repeatedly delayed meaningful progress against Alzheimer’s. As the field has rewarded confirmation of the amyloid hypothesis, suppressed dissenting hypotheses, and tolerated research misconduct, patients and families have borne the cost. The way forward, as advocated by Schrag and Piller, requires a broader view of disease mechanisms, honest reckoning with past errors, research integrity, and institutional reforms to revive genuine innovation.

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Further Reading

• Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s by Charles Piller
• Investigative articles in Science Magazine on Alzheimer’s research oversight

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For feedback or discussion, email [e-mail] or find Freakonomics Radio on social platforms.

Transcript

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[Stephen Dubner]

you may have seen the news recently about two new FDA approved blood tests that may detect Alzheimer's disease in the early stages. Early detection is important for any disease, but especially for Alzheimer's, which can take root for 20 years before symptoms develop. These symptoms, as you probably know, include memory loss and other cognitive, physiological and behavioral issues issues. The reason I say that you probably know these symptoms is because Alzheimer's affects more than 7 million people in the US most of them over 65. Age related memory loss has been seen throughout human history, but the disease was not formally documented until 1906 by the German physician Alois Alzheimer. When Alzheimer autopsied the brain of a woman who had had memory loss and hallucinations, he found that her brain had shrunk and withered with numerous tangles and what he called peculiar deposits. Scientists have been trying to figure out those deposits and tangles ever since. The National Institutes of health spends around $4 billion a year on Alzheimer's and dementia research. That's up from around $1 billion a decade ago, and that puts it second only to cancer spending, which makes sense because the elderly population in the US Is big and getting bigger. Much of this Alzheimer's research is centered around one dominant theory of the disease. But what if that theory is flawed?

[Charles Piller]

No one's getting better with these drugs. Every scientist who works with them, every clinician will say the same. If they don't, they're lying.

[Stephen Dubner]

So is flawed even the right word? Or should it be fraud?

[Matthew Schrag]

Cheaters tend to cheat when we find clear, overt problems in a paper in a group of papers. Often it propagates through somebody's entire work.

[Stephen Dubner]

Today on Freakonomics Radio, we follow an investigation that found decades of problematic Alzheimer's research. And we ask with some sense of earned optimism, where does Alzheimer's treatment go from here?

[Charles Piller]

This is Freakonomics Radio, the podcast that explores the hidden side of everything with your host, Stephen Dubner.

[Stephen Dubner]

The story we are telling today is a sobering one and an important one. We'll hear from two people. We had hoped there would be more, but in the end, the others did not want to talk. You'll understand why as we go. Let's start here.

[Charles Piller]

My name is Charles Piller. I am an investigative journalist with Science magazine and author of the book Doctored.

[Stephen Dubner]

The full title of Piller's book is Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer's. Charles Piller has been a journalist pretty much his entire adult life.

[Charles Piller]

I grew up in the Chicago area. I became interested in reporting kind of the way that so many people, boomers like me did, being inspired by the Watergate investigations. I was too young to be a journalist then, but not too young to be inspired and thinking about things, particularly during the Vietnam War period and all of the societal challenges there.

[Stephen Dubner]

Piller is 71 years old. Before coming to Science magazine, he wrote for the LA Times, the Sacramento Bee, and the Life Sciences news outlet stat. For the past several years, his reporting has been focused on Alzheimer's research. I asked him why?

[Charles Piller]

Well, the answer is, to me, pretty clear, and that is that unlike cancer, diabetes, heart disease, and myriad other ailments that afflict us, Alzheimer's disease is something that the nation and the world has spent tens of billions of dollars on in recent decades. And yet we have no remedy that arrests or reverses the terrible cognitive decline of the disease. And so even though there may be corruption in cancer research or in heart disease research, we've seen enormous advances in those diseases and sometimes even real cures for specific ailments that have benefited society dramatically. We have not seen that in Alzheimer's disease. And that makes not just more tragic but also terrifying for people who are facing those possible symptoms.

[Stephen Dubner]

What is the thinking on potential environmental drivers of Alzheimer's disease?

[Charles Piller]

Yeah, it's a great question. And I would say that care and prevention is one of the key things that I think our society should be increasingly concerned about. It's well known that people who are subject to highly polluted environments are experiencing Alzheimer's at a higher rate and also at a more severe age of onset, earlier age of onset Secondly, I would say that like so many ailments in our society, Alzheimer's is in part a disease of inequality. Now, of course, anyone from any economic level can get the disease, but it's more prevalent among people who do not have the same level of economic opportunities.

[Stephen Dubner]

To what degree would that be caused by less or worse medical care itself? In other words, how much advantage is there to early or constant monitoring and then whatever kind of treatment there may be? Or are you saying that low income people may have in their lives drivers that are responsible for Alzheimer's?

[Charles Piller]

I think it's both things. Clearly, problems like obesity are important in Alzheimer's disease. The other thing is that they found over and over that the higher educational attainment that people have, it has a benefit that can reduce the severity or the age of onset for the disease.

[Stephen Dubner]

Okay, so that was Charles Piller on a few potential drivers of Alzheimer's. So how does the disease itself work? For that, we need a neuroscientist.

[Matthew Schrag]

My name is Matthew Schrag. I'm an associate professor of neurology at Vanderbilt University Medical Center. I take care of patients who have strokes and memory problems. And I run a laboratory trying to understand how blood vessel diseases contribute to memory problems like Alzheimer's disease.

[Stephen Dubner]

Describe for me how much of your work is what a layperson like me might consider Alzheimer's related.

[Matthew Schrag]

Most of it. Our perspective is that blood vessel diseases contribute to Alzheimer's disease. We don't think of Alzheimer's disease as a blood vessel disease, but that's one of the issues that we've been working on is trying to understand the degree to which these other factors that have been largely overlooked may play a key role in how this disease works.

[Stephen Dubner]

So just walk me through quickly all the schools you attended and all the degrees you got.

[Matthew Schrag]

Yeah, I was at the University of North Dakota for my undergraduate work. And then I went to Loma Linda University and I got an MD and PhD there. And then I went to Yale for my residency work.

[Stephen Dubner]

Were you wanting to be this kind of scientist since the time you were a kid? Did your family or school or background encourage you?

[Matthew Schrag]

Not really. You know, this happened partly because I sat down with somebody when I started getting serious about trying to get into medical school and said, what are the things I should do to improve my odds of getting in? And one of the things they said is, well, you should do some research. I went and knocked on my professor's office and said, can I do some research? And he said to me, son, they didn't mean Botany. And so he very graciously didn't take advantage of me and shuttled me to a more appropriate laboratory.

[Stephen Dubner]

The lab that Schrag got shuttled to was run by a neuropharmacologist named Othman Grebe who studied Alzheimer's.

[Matthew Schrag]

I really enjoyed the atmosphere in the laboratory. I really loved the ways that you could try to study things that were too small to see and try to infer how complicated systems worked.

[Stephen Dubner]

The research that Schrag worked on with Grebe looked at the potential impact that diet could have on the onset and progression of Alzheimer's. In 2006, they and a few other co authors published a paper in the Journal of Neurochemistry Chemistry called Deposition of iron and beta amyloid plaques is associated with cortical cellular damage in rabbits fed with long term cholesterol enriched diets. So what was the idea of this paper?

[Matthew Schrag]

The idea of this paper was that cholesterol accumulates in the brain. We had raised a group of rabbits and fed them a high cholesterol diet, which was thought in some ways to mimic Alzheimer's disease. And the thought with this paper was that cholesterol levels would acc within the neurons themselves and that that could have a toxic effect on the neurons.

[Stephen Dubner]

Pretend that I know nothing about the neuroscience here, which you know, would be close to accurate. Can you just summarize the state of Alzheimer's research? What's known, what's not known, what's disputed.

[Matthew Schrag]

Alzheimer's disease is a complicated disease, but our current formulation of what happens in the brain is that there is an accumulation of these proteins that clump together. And two in particular, one is beta amyloid, or just amyloid clumps together outside of the cells of the brain, sort of in between the cells. And another protein called tau clumps inside of the cells of the brain. And that leads to the neurons eventually not functioning properly and eventually dying. And the brain shrinks and people begin to lose their memory.

[Stephen Dubner]

Where did the tau cells come in in that scenario?

[Matthew Schrag]

Tau is inside the neurons. It's a protein that is involved in the structure of a neuron. And if you think back to high school biology, you know, the neuron is this big compl that has a very long tail on it. It's one of the biggest cells in the body and they have to live for your entire life. And the tau protein is part of how the cell gets that unusual structure with the long tail that allows it to function like an electrical wire. So if you have tau clumped together and no longer participate in maintaining the skeleton of the cell. The cell doesn't function properly. So that's the second key piece of what's going on in Alzheimer's disease, that the neurons are structurally destabil, since I would say about 1990 in round numbers. The main thought in this field is that the plaques, this little beta amyloid protein that clumps outside of the cells, is the primary driver of the disease. And a huge amount of the effort related to drug development has been dedicated to preventing it from accumulating or breaking it up and clearing it from the brain. The general idea is that plaque is the first domino, and then there's a complicated series of events leading up to the neurons dying. But the plaque is the primary driver of Alzheimer's disease.

[Stephen Dubner]

This domino effect is known as the amyloid cascade hypothesis, and that is the hypothesis toward which many billions of research dollars have been directed. So what's the problem with that?

[Matthew Schrag]

The problem is, one, the idea may not be correct, and two, the biology of this is likely much more complicated. And I think that this is the primary issue is not that beta amyloid has nothing to do with what's going on, but. But most diseases at the end of your life are not simple. I can't think of another disease where there is one single first domino that falls that causes the rest of the cascade. By targeting just one very specific factor, I think we're not having a big enough impact on the disease.

[Stephen Dubner]

Schrag's own research, which looks at the connections between Alzheimer's and blood vessel diseases, is a pushback against the amyloid cascade hypothesis. And Schrag has also been pushing back as a whistleblower. I understand that outside of your work at Vanderbilt and your work within the academic community generally, that you also work as an independent research integrity consultant. Are all four of those words correct and in the right order?

[Matthew Schrag]

That's a good description of what I do.

[Stephen Dubner]

When you first started pursuing a career in academic research, is this how you envisioned it was going to work out?

[Matthew Schrag]

Not in the slightest, no.

[Stephen Dubner]

So how do you feel about it at this moment? If you could start again, would you pursue the whistleblower detour or no?

[Matthew Schrag]

I think I probably would, simply because of how I'm wired. But I think that initially, when I started down this road, I did it knowing it might have been a pretty

[Stephen Dubner]

colossal lapse in judgment for yourself, for your own career.

[Matthew Schrag]

That's right. But my viewpoint is that it's time for a direction change in this field. And I just think that sometimes you need to make a decision and just go with it.

[Stephen Dubner]

Matthew Schrag's first exercise in validating scientific research was unofficial. It came during his PhD training when he tried to reproduce the findings of a paper that had parallels to the rabbit paper that he had worked on as an undergrad with Othman Greeby. He found that the work was not reproducible. In 2021, this work took on a new scale.

[Matthew Schrag]

I was approached by an attorney and asked to help a group of whistleblowers investigate their concerns about the integrity of data underlying this drug, Simuiflam, which was being developed by a little biotech company out of Texas called Cassava Sciences.

[Stephen Dubner]

Cassava Sciences had been known earlier as pain therapeutics. They spent years trying to break into the opioid market. And then they switched their focus to Simufilam, an experimental drug for Alzheimer's. The company's research collaborator was a medical school professor at City University of New York named Haoyan Wang. His research had found that Simuphilim could reverse the misfolding of the protein filament A, which was hypothesized as a cause of Alzheimer's. Consistent with the amyloid hypothesis, Simufilam also promised to reduce inflammation by targeting the buildup of tau and beta amyloid in the brain.

[Matthew Schrag]

They had produced some data from their phase two trials that raised alarm bells for these whistleblowers.

[Stephen Dubner]

Who were the whistleblowers?

[Matthew Schrag]

They were a pair of scientists, a cardiologist and a neuroscientist who had some experience in this space and basically said they didn't think the pharmacology of this drug made sense, that there were some problems in the basic science that were just hard to interpret. And then when they looked at the image data, a lot of those photographs looked like they had been retouched. So I was paid a fee to help them research this and produce a document cataloging their concerns, but also to provide due diligence to the attorneys that were pursuing this.

[Stephen Dubner]

Was the case about these scientist whistleblowers trying to prevent this drug from going forward because they thought it would be ineffective and was based on misrepresented data. Was that the genesis of your involvement in this?

[Matthew Schrag]

It was certainly the driver for me to take the risk of speaking publicly on an issue like this. You take a substantial risk to engage on a topic like this against a multi billion dollar company.

[Stephen Dubner]

And where were you in your career at this point?

[Matthew Schrag]

Oh, I was very junior. I was an assistant professor, pre tenure, just getting started.

[Stephen Dubner]

How did you then get on the list of people to be called by an attorney representing these whistleblower scientists.

[Matthew Schrag]

I had given some interviews in the national media, and I think they were looking for somebody who was a bit outspoken perhaps, but also who had some credibility.

[Stephen Dubner]

Where did your credibility come from to that point?

[Matthew Schrag]

I had worked as an Alzheimer's researcher for quite a period of time at this point. And at the time, one particular drug, Aducanumab, was getting a lot of oxygen, and I had been talking publicly about some of the weaknesses of this approach to treating Alzheimer's disease.

[Stephen Dubner]

Okay, getting back to the Cassava Sciences case, the attorneys for the whistleblowers reached out, and you said the images looked like they had been retouched. Give me some detail there. The images just didn't fit what a scientific expectation would be. Did they look visually manipulated?

[Matthew Schrag]

It looked visually manipulated. Some of these results had copy and paste type changes where it looked like things had been moved around or duplicated, or where the intensity of one part of the image had been adjusted. And ultimately a lot of these results. How dark a splotch on the photograph is, is what we ultimately measure to turn it into data. So changing the intensity of those values changes the underlying data.

[Stephen Dubner]

To a layperson, that sounds like a sort of Mickey Mouse misrepresentation. And I don't mean to insult Mickey Mouse, but it seems kind of amateurish that to the naked eye, the images in a scientific paper could be seen to be manipulated.

[Matthew Schrag]

I don't know if you've had the experience of somebody showing you something and saying, what do you see? And you don't see anything, and then somebody explains to you what you're supposed to see, and now all of a sudden, you couldn't possibly turn the clock back and not see that. And I think there's some of that. I think once you've seen the patterns, you're right that they seem quite obvious. But I'll also say there's a difference between seeing something suspicious and being able to prove it. And that's part of what we were working on, was trying to do this in a very systematic and thorough way, and then also show that these are not random things, that these are not accidents or slips, but that there is a coherent pattern to it that changes the interpretation of the data.

[Stephen Dubner]

Tell me about who you worked with and what that work was like to look at these data and what your conclusions were.

[Matthew Schrag]

I worked independently, and once I settled in my mind that there was some legitimacy to these complaints, the next step was then to do some additional research and forensics on the material, on the scientific publications that were supportive of developing this drug and see if there were additional problems. And so I helped them build a dossier that was eventually sent to the the FDA to contest the continued development of this drug.

[Stephen Dubner]

And now it's in the FDA's hands. Maybe you're thinking that of course the FDA will follow your prescription because you had a lot of confidence in your data.

[Charles Piller]

Right.

[Stephen Dubner]

But I don't know. Did you have any skepticism that the FDA would wind it down?

[Matthew Schrag]

I was shocked that the FDA didn't take more action than they did. I expected within days for this to be a no brainer that this could not continue. And I was really surprised by the pace and the ultimate decision decisions. But one of the things that happened was we've noticed this pattern where cheaters cheat. That shouldn't maybe shock people. But when I started investigating this scientist, what we found is that the problems extended well beyond the work that he had done for this company. And so we had to decide what we were going to do with that. Obviously the attorneys were very interested in this company, but I felt like there was an additional scientific objective here to correct the scientific record more broadly. So we agreed that I would be permitted to continue to pursue the problems in the rest of this individual's work.

[Stephen Dubner]

I see. This is Haoyan Wang at City University of New York, is that right?

[Matthew Schrag]

That's right. Hao Yong Wang was the primary scientist working for Cassava Sciences. And so I ultimately sent a set of dossiers to the National Institute of Health describing more broadly the patterns that we saw in his work and in the work of his collaborators.

[Stephen Dubner]

And what did you hear back from the nih?

[Matthew Schrag]

Well, that's a very opaque process. So they thank you for your input and then you hear very little.

[Stephen Dubner]

One of the whistleblowers in the Cassava Sciences case reached out to a reporter at the prestigious journal Science who connected Matthew Schrag with a colleague of theirs, the investigative journalist Charles Piller.

[Matthew Schrag]

And it became clear to me he was looking to go a lot deeper than most of the reporters that I had talked to up to that point. My comments in the media had been mostly on background and my role had been as a consultant for this attorney and the whistleblowers he was working for. But obviously the story was bigger at that point. It was more than just Cassava Sciences. It involved a lot of scientists and, you know, the problem was expanding.

[Stephen Dubner]

Coming up after the break, we will hear how the problem expands. I'm Stephen Dubner and this is Freakonomics Radio.

[Matthew Schrag]

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[Matthew Schrag]

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[Stephen Dubner]

Before the break, the Vanderbilt neuroscientist Matthew Schrag described what he considered doctored research coming out of the biotech firm Cassava Sciences. The investigative journalist Charles Piller heard about Schrag's work and suggested that they collaborate. Here's Matthew Schrag.

[Matthew Schrag]

I agreed to show Charles the dossiers that I had prepared and had sent to the nih. And I had sent an additional dossier to the NIH about the issues at the University of Minnesota, which were incidental to the work that I was doing on Cassava Sciences. But I had become aware of this problem and had been dabbling with some image analysis techniques and and basically used this set of problem papers that I had found at the University of Minnesota as a test case to see how this technique would perform.

[Stephen Dubner]

One of these papers was a hugely influential study that had been published in the journal Nature in 2006. It was called A Specific Beta Amyloid Protein assembly in the Brain Impairs Memory. Among the co authors were two University of Minnesota researchers, Sylvain Lesnay and Karen Ashley. The research used genetically engineered mice whose brains produced excess amounts of amyloid protein. The researchers extracted that protein from the mice and injected it into the brains of rats, who soon after showed signs of cognitive decline.

[Matthew Schrag]

This paper came along at a moment where the amyloid hypothesis had a big stumble. A clinical trial looking to remove beta amyloid from the brain with a vaccine, which, frankly, is a really clever approach. But the trial failed. And sometimes really good, really clever ideas don't work, and this was one of them. And people started questioning whether this was the right hypothesis. So this reformulation came along that perhaps it wasn't the big clumps, the plaques of beta amyloid that was the primary driver of the disease. Perhaps somewhere in between a single molecule of beta amyloid floating around, and where it was millions of these molecules in a giant clump, perhaps there's some soluble small clump of beta amyloid that was the toxic component. And they call those oligomers, which is just Greek for small clump, I guess. Sylvain Lesney proposed that he had found that silver bullet, that a clump of a certain number of strands of beta amyloid was the primary cause. And his paper was cited and continued to be cited right up until we challenged it.

[Charles Piller]

This experiment gave new confidence to people in the field and became one of the most cited experiments in the history of the disease through 2022.

[Stephen Dubner]

That, again, is the journalist Charles Piller. So what happened next?

[Charles Piller]

Schrag and I started to look carefully at this, and ultimately I wrote a story about it in Science magazine.

[Stephen Dubner]

The major issue they found with the paper by Lesney and Asch had to do with the images that were used

[Charles Piller]

as evidence, primarily in this case. It involves something called Western blot images. Now, these are a very, very common technique used in science, particularly often in Alzheimer's research and in other fields as well. And what they are are a photographic representation of proteins, so you can test a protein sample for the type and amount of different proteins within it. This is very important in Alzheimer's research because you're trying to determine what proteins are in an animal brain, for example, that might be behind the disease in some way. And so what Schrag found from his work, and this was validated by other forensic image experts by me going to them, and also by leaders in the field of Alzheimer's research. What was found was that these images apparently were manipulated in severe ways that tended to support the hypothesis of the experiment when the actual data did not support it.

[Stephen Dubner]

So I assume that you contact Lesnay what's that conversation like?

[Charles Piller]

That conversation is one that regrettably never occurred because he wouldn't speak to me.

[Stephen Dubner]

Okay, and what about Matthew Schrag, your co investigator? Did Lesnee or anyone else from his lab, including, I guess, Karen Ash, did they speak with Schrag or respond to any comments? Is he sending them information about his charges of manipulation?

[Charles Piller]

I mean, Shrag's a scientist. I was the one who, as a journalist writing the article, of course, I did everything I could possibly do to get Lesney and his co investigator, who at the time of the experiment was his boss, Karen Asch, to speak to me. Prior to the article appearing, they both refused to speak with me. This is detailed in my book and also in the article that I wrote about it. And it was, I think, not that surprising in a way. I found over many years of experience doing these sorts of articles that people don't have a great story to tell, often are unwilling or unable by their institutions, restricting them from saying anything to a reporter. Ash, I did have a dialogue with and she very interestingly replied that she wanted to talk with me, but her university advised her not to and she decided that she would go along with their advice. I explained to her at the time that I thought it was terrible advice because this was her opportunity to get her perspective into the most read deepest look at the subject.

[Stephen Dubner]

The thing that frustrates me about that is universities are also part of the public trust and they get a lot of research funding from taxes. And so I feel like it should be incumbent upon them to at least respond, at least take the charges seriously. When you found that you weren't getting a serious response from her, what was your next step then?

[Charles Piller]

In this case, what happens is the National Institutes of Health, which is the funder of this work, take a look at it. They agreed that there was a possible problem there. They referred it to an obscure government agency called the Office of Research Integrity at the Health and Human Services Department. This is a tiny little group. They don't have the manpower to examine every possible example of fraud or misconduct in the scientific world. And so what they do is they give it back to the university where the alleged misconduct took place, in this case, the University of Minnesota. To me, this is, is exactly the wrong approach because you're entrusting the organization that has the most to lose and the least to gain from a robust, complete and publicly accessible examination of possible misconduct to do that examination. So they took years to assess Lesney. In the meantime, he was still collecting many hundreds of Thousands of dollars in federal funds to continue the same lines of research that had already been proved questionable, and I might add, published a paper after my initial story came out that we found had apparently manipulated scientific images in it. This goes on and on, and the university is going about their business. Finally, in 2025, Lesney retires from his job. He resigns from his post as a tenured full professor. This is a pretty young guy. So what you're talking about is a guy who ended his scientific career, in effect.

[Stephen Dubner]

What was the extent of that university investigation?

[Charles Piller]

Well, we'll never know because they never released any of the particulars, except to say that they had asked for journals to consider retracting other Lesney articles. Now, the initial story, this seminal paper in Nature that was influential in the field of Alzheimer's disease, and I would argue, and I think many people agree, had a very, very high degree of importance in moving the field forward. This paper was retracted. Ultimately,

[Stephen Dubner]

it was co author Karen Asch who formally requested that the paper be retracted from the journal Nature. In a note she published elsewhere, Ash acknowledged problems with the data, but said she had had no knowledge of it until it was brought to her attention. We reached out to both Karen Ash and Sylvain Lesne. Lesne declined to speak with us, and we didn't hear back from Ash. And what about Cassava Sciences and their experimental Alzheimer's drug, Simufilam? Charles Piller and Matthew Schrag kept digging into that as well. Piller published an article in Science about an internal report from the City University of New York, which found numerous signs of image manipulation in Haoyan Wang's work and bad Data Management. In 2024, the Department of Justice indicted Wang for allegedly fabricating and falsifying data in NIH grant applic related to Simufilam. Wang faced multiple charges, including major fraud against the United States, wire fraud, and false statements. A few months later, Cassava Sciences agreed to pay $40 million to the securities and Exchange Commission to settle charges that it misled investors on the effectiveness of Simufilam. Cassava stopped development of the drug after publicly stating that it had failed in human clinical trials, showing no cognitive advantage over a placebo. Cassava President and CEO Remy Barbier and senior Vice president and neuroscientist Lindsay Burns both resigned. And last month, Cassava Sciences announced that it was once again changing its name, this time to Falana Therapeutics. Haoyan Wang also agreed to pay a fine related to the SEC charges. And in 2025, all charges of fraud made by the DOJ were dropped. We tried to reach Huang and got no response directly. But his lawyers said they are pleased that the case against Wang was dropped in light of new evidence and maintain that Wang is innocent of the accusations made against him. We also reached out to Falana for comment. A spokesperson for the company said they are currently focused on researching and developing a treatment for a rare form of epilepsy. Meanwhile, Charles Piller, as part of his book research, had been looking into the track record of many Alzheimer's researchers.

[Charles Piller]

I focused on about 50 who were both influential and who seemed to be people who needed a closer look. Probably the most interesting one is this guy, Eliezer Mazlya, who was previously the head of the division of neuroscience for the National Institute on Aging. This guy was overseeing a budget of about about $2.7 billion per year. And this made him one of the most influential people in the world by far to steer the agenda of neuroscience research because this is the biggest funder worldwide for this work. He for decades had been a researcher at the University of California in San Diego. He became an eminent scientist in both Parkinson's and Alzheimer's research. So when he was hired to be the head of the neuroscience division at N, it made him a logical choice. Someone who had respect, had contacts, had prestige, had himself demonstrated a propensity for influential research. And he operated his own lab within NIA as well as directing their programs.

[Stephen Dubner]

And at that time, were there any suspicions of research misbehavior or image doctoring?

[Charles Piller]

No, there were no suspicions of him, according to the nih. So with the cooperation and assistance of four leading forensic image experts, and that included Matt Schrag, a woman by the name of Moo Yang, who is at Columbia University, who's becoming a pretty well known forensic image expert. Also Kevin Patrick, who is not a scientist but is an independent researcher who is excellent and very seasoned at looking at these images. Elizabeth Bick, who is a world renowned expert in in scientific image analysis. And the four of them took a look at Maslia's papers. We found 132 papers out of the 800. We didn't look at all 800 because it was too massive a task at 132 where image irregularities, including apparently doctored images, apparently misused or reused images, apparently images that were published separately in different papers in an improper way to make different scientific points. What came out of it was a 300 page dossier detailing all of the concerns. And this traces back to Masli's work going back 30 years, including at UC San Diego, and also the work coming out of his lab at the National Institute on Aging.

[Stephen Dubner]

Work that he's directing personally.

[Charles Piller]

That he's directing personally in his own lab.

[Stephen Dubner]

So you compiled this Dossier that identifies 132 papers with signs of apparent image doctoring. How do you present this information to him and what's his response?

[Charles Piller]

Well, in the most straightforward way possible, I wrote to him, I presented the dossier to him. He had 100% of the information. I asked him a wide range of questions about the problems that we found. And of course, we offered him the opportunity to present evidence that would suggest that we had it wrong in some way. And so the response was that he didn't respond. The response from the agency was at first they would refuse to respond, and then as the date of publication became closer and closer, literally three days before the story was published, they said, wait, wait, we might have something for you. And then they timed their announcement about this to land the moment my story went live on the Science magazine website. And that announcement was that Maslia was no longer in state a job.

[Stephen Dubner]

Eliezer Maslia declined to speak with us, and the NIH sent us a statement to say that they do not comment on personnel matters. Coming up after the break, Matthew Schrag has a reckoning with his former mentor. I'm Stephen Dubner. This is Freakonomics Radio. We'll be right back.

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[Stephen Dubner]

You said you were directed to a lab where you were an undergraduate University of North Dakota, and there was someone, I guess, running the lab. Right. Othman Greeby, who became really a mentor of yours, correct?

[Matthew Schrag]

Yeah, absolutely. He taught me an awful lot and became a very good friend.

[Stephen Dubner]

Turns out that he was one of the people that you blew the whistle on. The hardest. Yes.

[Matthew Schrag]

Yeah, I mean, it was a very disappointing end to our relationship.

[Stephen Dubner]

This, again, is Matthew Schrag. He told us earlier about this research with Greeby looking at plaque buildup in the brains of rabbits who'd been fed a high cholesterol diet. I asked Schrag what his role had been in this research.

[Matthew Schrag]

Well, I helped raise the animals and I helped sustain the tissue. After the work with Cassava Sciences, I very much expected that every paper I'd ever looked at was going to get analyzed and dissected, but I wasn't aware of problems.

[Stephen Dubner]

What do you mean by that? You expected that every paper would get dissected?

[Matthew Schrag]

I expected that people I was blowing the whistle on would have a good, hard look at my research and make sure that my work was clean.

[Stephen Dubner]

I see.

[Matthew Schrag]

And I was quite astonished when somebody reached out to me and said, have you looked at these images from the first couple of papers that you ever published?

[Stephen Dubner]

What were the images?

[Matthew Schrag]

They were microscope images. So we were looking at a field of neurons. The suggestion was that the neurons looked too much alike. It looked like some of them might have been copied and pasted multiple times.

[Stephen Dubner]

So who was it that, in your view, took and manipulated those images before they were published in the paper?

[Matthew Schrag]

Well, that happened at the hands of my mentor, Othman Greaby. And I know this partly because he was responsible for the paper and put the figures together, but also partly because when I asked him about it, he. He told me, this is years later. This is when we discovered the problem. And I have to say that once these images were brought to my attention, I looked at everything. In fact, I recruited a couple of other experts in this area to help me so that we could do this fairly quickly. I also felt it was important to have an unbiased set of eyes or two, because I certainly felt that I was partial to Othman. We very rapidly went through everything we published together, but also everything else that he had published.

[Stephen Dubner]

And how much of it had problems?

[Matthew Schrag]

Unfortunately, just an enormous portion. And, you know, the types of problems were the sorts of things that were

[Stephen Dubner]

very hard to dismiss, meaning manipulated imagery and so on.

[Matthew Schrag]

That's right. And in a way that was coherent in changing the interpretation of the results. I have to say, when I talked to Othman about it, he said that he thought the underlying science was right and that he was trying to make it a little bit clearer and said it was more exaggeration than manipulation. You hear these kinds of ways of sort of shrinking the problem, but when you looked at the pattern, it was very hard to ignore. I have to say, it took me a little bit of time to settle that this was going to be a huge problem because I knew Othman. I just assumed that this was a mistake. So my initial reaction was, hey, we're seeing these problems in these initial couple of papers. And I didn't know the scale of it at the time. I basically said, hey, let's track down the source data and fix it. I reached out to him to try to do that. I reached out to the university to see what sorts of things might still be around. But the problem was that at some point, Othman had gotten rid of all of his records. I think he knew that this was a problem. And he told me he was very ashamed of what had happened. And so at some point he closed his laboratory and disposed of everything in part out of shame of knowing that this data was not at the standards that. That he expected of himself.

[Stephen Dubner]

So when you called him, ultimately, what was that call like?

[Matthew Schrag]

It was tough. It was a very tough call. Initially, he said that he wanted to speak out and exonerate me from being part of the problem, which I appreciated. But also, I don't think most people would look at the middle author of the paper, who's an undergraduate, and say, that's the bad guy. I don't wanna say that never happens, but it's unlikely.

[Stephen Dubner]

So did he speak out?

[Matthew Schrag]

He had some initial conversations with people and he sent me some things in writing to say what he. But ultimately he decided not to speak publicly, which I just thought was a really sad mistake. I told him at the time, and I still think that he was a wonderful teacher. And a lot of times people who have trouble in one domain can still have a lot of value to bring to the table. I told him that if he could find it in himself to speak out about this and talk not just about what happened, but why it happened and why other people might experience this and the Importance of really hanging onto the basic principles that we as scientists all sign up for, that his role as a teacher could just be exponentially more important. And I still sort of hope that he would do that someday.

[Stephen Dubner]

I understand that there'd been an earlier misconduct inquiry into his work back in 2006 or 2007. Do you know anything about that?

[Matthew Schrag]

I do now. I didn't at the time. Apparently it actually involved this paper that we're talking about. Some of the problems had been picked up in a grant review is the story that I was told. Othman told me this story eventually that they had picked up on some anomalies in the data and they had referred it both to the university and to the journal. And the journal asked him to send original images so that they could inspect them and insisted on a correction to the paper. They did publish a correction. The correction was fairly vague in terms of what had happened. And so. So it was presented as a simple accident.

[Stephen Dubner]

Did you ask him why he did what he did?

[Matthew Schrag]

You know I did. And his point of view at that time was that he wasn't making anything up, that he was trying to make the images more convincing or easier to understand. But he equated it with a bit of an exaggeration rather than whole scale fabrication, which I must say in practice is no different. But that was his perspective. His perspective was also that everybody did this, which is not true. And we have to say that. We have to say that it's easy to erode the standards, but we have to consistently say no, not everybody does this.

[Stephen Dubner]

Okay, so you were a kid when you worked with him and now you're an actual academic.

[Matthew Schrag]

I have to say though, he remained an important person in my life. When I moved universities, he stayed on my dissertation committee. So he remained an advisor. He came to my graduation and went through all the regalia, putting the hood on me. You know, he came to my wedding. And so this was somebody who was more than just a passing academic acquaintance. And I think that's important when you think about these kinds of stories is that there's also underneath all this, often a very personal story. These are real human beings who are often very attached to each other. So it's easy for people to say, why don't people take a stronger stand? But I know how hard it is to take that stand, that it often has a real human cause.

[Stephen Dubner]

The 2006 rabbit paper by Grebe Schrag and three other CO authors was retracted in 2020. Three other joint papers from Schrag and Grebe were retracted soon after along with a few more Greebe papers. Since 2022 Grebe has been teaching at the University of Texas, Rio Grande Valley. Of all the Alzheimer's researchers that we contacted who had been accused of wrongdoing doing Othman, Greeby came closest to sitting for an interview. But ultimately he declined. He did send us an email. He wrote research is teamwork and I stand by the data, at least most of it. Of my research no fabrication was made but some polishing could have been done. However, I take full responsibility as I am the laboratory director. He also wrote, I insist that the imaging figures in Dr. Schrag's two manuscripts from my lab are the images he handed to me. He had many years to question the pictures if he believed they were altered. Grebe also told us that he lost access to his lab and his data after retiring from the University of North Dakota in 2020. The journalist Charles Piller told us that he tried to speak with Grebe before Pillar published an article on these allegations in Science. Pillar said that Grebe agreed to an in person interview. But back to out a few days prior I went back to Charles Piller with some more questions. You write that Alzheimer's research has essentially been hijacked by a cabal of self interested researchers, government accomplices and corporate greed. That's pretty dramatic Charles. I can imagine that some ears hearing that immediately go to conspiracy theories territory. Persuade me that this is not conspiracy theory that you're floating here. That the researchers, government accomplices and corporate greed are spoiling the pool for everyone here. And that this is based on research and reporting and actual empirical arguments.

[Charles Piller]

Just to put it plainly, nearly all of them have built their careers on explaining, exploring and expanding the benefits and the importance of the amyloid hypothesis. Their money, their prestige, their career aspirations are all tied up with that.

[Stephen Dubner]

You write that 11 of 16 FDA medical examiners who worked on drug approvals left to become employees or consultants for the companies that they just regulated. Public Citizen has concluded that regulatory capture has now infiltrated the fda. Tell me a little bit more about that.

[Charles Piller]

Well let me give you an example in the Alzheimer's field that I think is very instructive. The first of the anti amyloid antibodies that was approved by FDA was a drug called Aducanumab. That's the scientific name. The trade name was Aduhelm. It's been withdrawn from the market. The reason it was withdrawn is that it was dangerous and ineffective. This drug was essentially the product of regulatory capture. The guy who was overseeing the the shepherding of it through the fda, his name is Billy Dunn, was found in a journalistic investigation by the website Stat, and then later by a monumental US Congress investigation to have been working hand in glove with the company that was promoting and trying to get the drug approved. Billy Dunn left the FDA shortly after this episode. And what did he do? He took a big job as a member of the board of a biotech company developing Alzheimer's and Parkinson's disease remedies. There's many, many other examples. And this has been described as a revolving door at the fda. This is one element of the Trump administration program that is being championed by Marty Makary, who's the FDA commissioner that I think is really smart, which is to try to reduce this revolving door phenomenon. There's too many conflicts of interest in drug development. So, yes, I think that's a real problem that needs to be correct.

[Stephen Dubner]

How do you think about your role at a time when there is a growing distrust of science? In some places, including some places within the federal government, a lot of your reporting has been shining a light on misbehavior, which you could argue might destroy trust even more. So how does that change the way you work?

[Charles Piller]

Yeah, thanks for the question, Steven. I think about this a lot. I just want to make it clear that I really disagree strenuously with a lot of the moves being made by the Trump administration regarding science and research. I think it's important for universities to have freedom to pursue science and scientific research in a vigorous way without feeling that they have to knuckle under to federal demands for certain kinds of political issues. I also disagree with the way in which attacks have been made on federal research funding at the nih. The administration is not wrong about everything and, and critics of the scientific enterprise are not wrong that there has been arrogance and complacency and in my view, condescension on the part of many people in the scientific research enterprise towards members of the public.

[Stephen Dubner]

Condescension along the lines of trust us, we're scientists.

[Charles Piller]

Yeah. I mean, trust must be earned. Now, let me make it clear that two things can be true at once. We can be highly critical of attacks on science and attacks on the scientific enterprise by people who I think are misguided. And at the same time, we can insist that the institutional authorities of science, and by that I mean the gatekeepers of knowledge, like the universities and journals like the one I work for, and the funders like the National Institutes of Health and the Regulators like fda, we can insist that they do better at their jobs, that they be more vigilant and more careful and also be more responsible for protecting scientific knowledge from pollution by bad ideas and corruption.

[Stephen Dubner]

We spoke with a few people on background who have been the focus of your research. One person said, sorry, I am tired of this. It is a non story. The anti amyloid treatments are working now. Tens of independent confirmations. Pillar you is merely on a book choreography response to that. Is it indeed true that anti amyloid treatments are working, that there are tens of independent confirmations of that research?

[Charles Piller]

So anti amyloid antibodies. Now there are two approved drugs by the FDA and these are drugs that remove amyloid proteins. With regard to how effective the drugs are, I think there's evidence that they can very slightly slow the cognitive decline associated with Alzheimer's disease. Although there are many clinicians who say that the degree of slowing compared to people who are not on drugs is so subtle that it can be imperceptible to clinicians, patients and family members. So no one's getting better with these drugs.

[Stephen Dubner]

On the other hand, if I'm a scientist, whether working on this particular research or other research, I might say, well, Charles, you know better than most people that science is really hard. Alzheimer's is a disease that's been with us for it sounds like pretty much all of human civilization and you need to take these incremental steps to try to find provable directions, at least of better clinical treatment. What would your response to that be? Is it that this is just not the viable path towards success? Or that it may be, but after all these years and all this money, that if there hasn't been more credible improvement then we should really be looking elsewhere.

[Charles Piller]

I don't think that things are mutually exclusive. Stephen, what I would say, and contrary to what some critics of my book have described it as, in which I would regard a strawman arguments, I have never said that amylate proteins have nothing to do with Alzheimer's disease. I have always said that they don't have everything to do with it and that it's important for people to understand that Alzheimer's is almost certainly a disease of many factors and it will almost certainly require many different approaches, perhaps in combination to result in any sort of remedy that arrests or reverses the symptoms of the disease. Now, what concerns me about the dominance of anti amyloid antibodies within this field is a is that one, they're very expensive. Two, they are dangerous. They can cause brain swelling and bleeding that has on occasion resulted in death Third, they're not effective in arresting the symptoms of the disease. And fourth, it's very important to understand that when this idea, with its incredible dominance over decades, soaks up a lot of the mind share and a lot of the ideas behind drug development and a of lot of the big money behind Alzheimer's drugs. In other words, if you look at the range of clinical trials, you'll see that a lot of things are being tried. But if you look where the big money's being spent, it's predominantly in anti amyloid remedies that we know from historical experience are not that great.

[Stephen Dubner]

I went back to Matthew Schrag to ask what he thinks the future looks like for the research and treatment of Alzheimer's disease.

[Matthew Schrag]

I would reformulate Alzheimer's disease and perhaps a number of other neurodegenerative diseases too, as diseases of failed waste clearance in the brain, that you have an accumulation of waste products in the brain. Beta amyloid plaques are one of them and tau tangles are one of them. And I think that thinking about this in a more complete way helps that saying that this isn't one specific thing causing the problem, but that we have a problem with waste management and that the accumulation of all of these waste products is adding up to a toxic sphere. And if you reformulate it that way, you can explain the clinical trial results that we've been getting with the amyloid therapy, which basically says this is one of the waste products. And perhaps there's some sort of minimal benefit from clearing one of the waste products. But we need to take a bigger approach and there's a lot of different ways of getting rid of waste products. One of them is through the blood vessels. You can actually wash it out of the brain by washing it through the blood vessels and so on. Our and a number of other labs too have theorized that degeneration of the blood vessels slows down that process of clearing waste products out of the brain. And so if we could focus on blood vessel health, we may get somewhere. And actually we have a hint of that in the clinical trials. The one real bright spot in the clinical trial space is that aggressive blood pressure control seems to prevent protect memory, especially early on.

[Stephen Dubner]

Early on, meaning what?

[Matthew Schrag]

Like before people's memory has deteriorated. So if you get patients at the very first sign of memory problems, or likely even before that, we see some benefit in memory. And I think it's pointing at blood vessel health being a big part of keeping the brain healthy.

[Stephen Dubner]

Is Alzheimer's curable?

[Matthew Schrag]

I don't know. I would like to think so. It's certainly a complicated disease. And I think that there had been a certain nihilism about neurological diseases in general. They used to say about neurologists that we could diagnose the disease but not treat them. They would say that we were the diagnose and adios, doctors. But over the last few decades, we've seen a real renaissance in neurology and neuroscience. A lot of diseases that have been hard to treat, we're seeing very good treatments developed. We see that in a pretty dramatic way with epilepsy. We've got quite a long list of treatments now, including many patients being able to be surgically cured. Stroke has completely morphed in my career. This was one of the most depressing service lines in the hospital. Somebody would come in with stroke and be horribly disabled. And now, if patients can get to us in time, we're often able to do huge amounts for them. And so I think we've seen a bit of. Of a renaissance in neurology and neuroscience, but it's missing in the neurodegenerative space. And I have to ask the question, to what degree research integrity issues have held back development here. People described how hard it was to get funding if your ideas didn't conform with this hypothesis.

[Stephen Dubner]

I have to tell you, Matthew, when I first started doing this Freakonomics work, I signed up for a whole bunch of academic journals, mostly within the realm of econ. And I got some neuroscience journals because I thought the brain. Brain's pretty important. I'm interested in this kind of stuff. I should really read these. I couldn't. It was so complicated. I felt like if you didn't have at least a PhD to start with, it was just totally indecipherable. On the other hand, everybody listening to this has one. A brain that is. And so I do wonder if you, as an expert, have any advice for how to think about the brain and its centrality to who we are as individuals, but especially how we should think about brain science as a topic that we should all be a little bit invested in somehow.

[Matthew Schrag]

You know, the brain is a wonderful, beautiful organ. And I have to say, all of that complexity of the way we talk about it aside, if you sit somebody down on a microscope and the thing. See these neurons with their own eyes, it is just one of these really moving experiences. It's incredibly, beautifully organized organ that allows us to access who we are. And it's an organ that we have a lot to learn about. But we do know a few things. One is that we need our memories to last a lifetime, to really get everything out of life that we're trying to get out of life. We've seen incredible progress in other fields of medicine that has expanded life expectancy over the last century or century and a half. A lot of the benefit of those advances are being lost to this disease. If those extra years that you're getting at the end of your life are of poor quality, this is something that affects all fields and a huge number of people. This has affected our political leaders and our musicians and our sports figures and almost every family in this country. I think that it's easy to accept this as just a part of old age and say there's nothing we can do about it, but I think there must be something that we can do about it. This is one of the challenges for our generation, is to crack the code on this set of diseases, to make sure that the quality of life at the end of the life is what it should be.

[Stephen Dubner]

So, Matthew, when you look back at your career, it seems from my perspective that you're doing well. You're at a great research university, Vanderbilt, but you've also devoted a lot of time and attention to this whistleblower function. How would you describe overall your standing in the field as a result of the whistleblower function? Do you feel you've been somewhat ostracized, mostly celebrated? A good bit of both.

[Matthew Schrag]

There's definitely been some degree of backlash, and I think that's expected and almost unavoidable. Some opportunities lost, but I think that's okay. There's also other opportunities gained. The ability to have important conversations about where our field is going is a unique opportunity that I wouldn't give up.

[Stephen Dubner]

Does anyone in your family ever say to you, you know, Matthew, it'd be so much easier if you just stick to your knitting, do your research, shut

[Matthew Schrag]

up a little bit.

[Stephen Dubner]

Did anybody say that?

[Matthew Schrag]

I will say that I sought the advice of quite a number of advisors before agreeing to go on the record with Charlie. And I don't think anybody thought it was a good idea. He's a very thoughtful person and I think a very, very cautious person. And I think that that's key. There's a huge amount of trust that you put in somebody by doing this.

[Stephen Dubner]

I'd like to thank Matthew Schrag and Charles Piller for putting their trust in us and telling you this story. I do wish that some of the scientists whose work they had exposed had also been willing to talk, but I guess I can see why they chose not to the book that Charles Piller wrote is called Fraud, Arrogance and Tragedy in the Quest to Cure Alzheimer's. If you want to let us know what you thought of this episode, Our email is radioreconomics.com we are also on all the regular social platforms, even a few of the irregular ones. Coming up next time on the show, we go inside one of the most essential software companies that you have probably, probably never heard of.

[Charles Piller]

I had no interest in starting a company. I had no idea how to do it.

[Stephen Dubner]

Judy Faulkner is founder and CEO of Epic Systems, which manages the vast majority of electronic health records in the United States. She doesn't do a lot of interviews, but she agreed to this one and we cover a lot of ground, including why Epic has never gone public and never will.

[Charles Piller]

The shareholders were only interested in return

[Stephen Dubner]

on equity, not what value the company

[Charles Piller]

was giving to the world. And I thought, who wants owners who are like that?

[Stephen Dubner]

That's next time on the show. Until then, take care of yourself and if you can, someone else too. Freakonomics Radio is produced by Renbud Radio. You can find our entire archive on any podcast app. It's [e-mail] where we publish transcripts and show notes. Notes this episode was produced by Dalvin Abu Aji and edited by Ellen Frankman. It was mixed by Eleanor Osborne with help from Jeremy Johnston. The Freakonomics Radio Network staff also includes Augusta Chapman, Elsa Hernandez, Gabriel Roth, Hilaria Montenicourt, Jake Loomis, Mandy Gorenstein, Peter Madden, Teo Jacobs and Zach Lipinski. Our theme song is Mr. Fortune by the Hitchhikers and our composer is Luis Guerra. As always, thanks for listening. I see that you live on what's called a hobby farm outside of Nashville and that you do beekeeping.

[Matthew Schrag]

Yes, I did that for a number of years. It was a great pleasure. Keeping bees with the last baby, I let the bees go.

[Charles Piller]

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