Alzheimer’s disease research, between fraud, arrongance and hope

Nearly seven million Americans live with Alzheimer’s disease, a tragedy expected to cost the country nearly $1 trillion a year by 2050. While families suffer and are haunted by promises of pharmaceutical break­throughs that routinely disappoint, investigative journalist Charles Piller shows in Doctored that we’ve likely been pushed into dead ends to finding a cure all along. Shedding light on a cabal of self-interested researchers, their government accomplices, and ever-present corporate greed, Doctored shares how Alzheimer’s patients and their loved ones have been sacrificed for careerism and profit.

Reference: www.simonandschuster.com

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In your book Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s, you argue that Alzheimer’s research has been hindered by scientific fraud and a kind of academic “mafia.” What are the most compelling pieces of evidence supporting this claim?

Doctored describes work by a small team of unpaid forensic image experts, who uncovered hundreds of problematic – or fraudulent – papers from dozens of Alzheimer’s investigators (the widespread diffusion of image editing software has created the need for digital forensic techniques capable of blindly detecting the presence of image forgeries. This is particularly significant for scientific images, such as western blots which are used in molecular biology to detect specific proteins in biological samples, Ed. Note). Those papers have been cited in the scientific literature about 80,000 times. The apparently doctored studies also have been cited in active patents nearly 500 times. The investigation exposed strong evidence of misconduct by numerous established investigators, including undeniable leaders of the field, and had direct implications for multiple clinical trial programs. The book describes how the influence of powerful figures in the field who support the supremacy of the amyloid hypothesis have forced many scientists to adjust their own ideas that might run contrary to it.

For background, I refer you to my recent New York Times essay “The Devastating Legacy of Lies in Alzheimer’s Science“:
Even many of the most hardened skeptics of the hypothesis believe that amyloids have some association with the disease. But since the early 2000s, doctors, patients and their loved ones have endured decades of therapeutic failures stemming from it, despite billions of dollars spent in grants and investments. Its contradictions — such as the presence of massive amyloid deposits found in the brains of deceased people who had no symptoms of Alzheimer’s — have long exasperated critics and prompted doubts among many supporters.
Still, the hypothesis retains enormous influence. Nearly every drug approved for Alzheimer’s dementia symptoms is based on it, despite producing meager results. The anti-amyloid antibody drugs approved in the United States cost tens of thousands of dollars per patient per year, yet they slow cognitive decline so minutely that many doctors call the benefits imperceptible. The drugs are also not benign, posing risks of death or serious brain injury, and they can shrink the brain faster than Alzheimer’s itself.
The entrenchment of the amyloid hypothesis has fostered a kind of groupthink where grants, corporate riches, career advancement and professional reputations often depend on a central idea largely accepted by institutional authorities on faith. It’s unsurprising, then, that most of the fraudulent or questionable papers uncovered during my reporting have involved aspects of the amyloid hypothesis. It’s easier to publish dubious science that aligns with conventional wisdom.

Some critics argue that Doctored overstates the impact of scientific fraud on Alzheimer’s research and drug development. How do you respond to those who claim that science is inherently self-correcting and that overall research progress has not been significantly compromised?

See the above answer for some data. People might disagree on the impact of apparent and actual fraud on the field, but clearly the problem is large. It’s reasonable to think that a broader, deeper look at the field (beyond what was feasible to do for a book of this kind, relying on volunteer forensic image analysts) would uncover further problems.
I also believe that science is self correcting in the long run, as I write in the book. For example, Matthew Schrag, a key source for the book, is quoted as saying: “You can cheat to get a paper. You can cheat to get a degree. You can cheat to get a grant. You can’t cheat to cure a disease. Biology doesn’t care.”
But due to the complacency and self-interest of many journals and powerful figures in the science, “self correction” when fraud or apparent misconduct occurs can take years or decades. This was documented for many cases in my book. As many other have said, it can be difficult or impossible to publish negative results, especially when they cast doubt on well accepted experiments conducted by famous scientists. That weakness of scientific publishing is part of the problem.
Therefore, the slow self-corrective process often fails to prevent misconduct from skewing thinking in the field, wasting precious funding, and even harming or exploiting patients. And too often, self-correction depends on whistleblowers who take a stand for integrity at serious personal risk.

Your book has received significant media attention and even had real-world consequences, such as participants withdrawing from clinical trials. Did you expect such a strong reaction? What could be the long-term implications?

Advocates of anti-amyloid antibodies might underestimate people who live with genetic signs that they could someday become Alzheimer’s patients, patients who show early signs of Alzheimer’s (and their loved ones). Those at risk for Alzheimer’s, or living with early stages of the disease, are perfectly capable of assessing the risk-benefit ratio of experimental drugs if provided with credible information.
My book describes those risks and benefits regarding anti-amyloid antibody drugs, as my prior reporting in Science did. Of course, I stand by the reporting in the articles and in the book, which is supported by information from the clinical trials and other scientific writings, and from the views of noted experts in Alzheimer’s disease. Bear in mind that critics of my work do not identify incorrect facts about the risks and benefits of anti-amyloid antibody drugs. They differ with ideas about what that information might mean for patients and for scientific research. If the ideas of advocates of the anti-amyloid approach to Alzheimer’s disease were as certain as they say, a book by a journalist should not provide a formidable challenge.
I’m happy if my work has provided helpful information for patients (and their loved ones) to calculate their own appetites for personal risk versus the possible benefits of the drugs. However, you should check the data on the adoption of anti-amyloid antibody drugs since their introduction long before my book appeared in February of this year. The uptake by patients has been slow – very distant from the blockbuster expectations of these “breakthrough” medicines, as described by boosters. To blame skepticism about the drugs solely on my book seems to ignore the market realities they are facing.
I’m unsure what you are asking about long-term implications. But I hope that a wide range of ideas and possible treatments for Alzheimer’s are developed, including continued study of the role of amyloid proteins in the disease.

Do you believe that the focus on the amyloid hypothesis has indeed slowed down research into other potential causes and treatments for Alzheimer’s? In your view, what are the most promising directions that research should explore?

I do think the intensive focus on the amyloid hypothesis has slowed other research, as detailed in my book. But I have never said that all other research ideas have been frozen out. I’m not an expert on all forms of research in the field, but some examples of potentially promising ideas are covered in Chapter 22 of my book.

It seem that sometimes FDA burys evidence of scientific fraud and misconduct, keeping critical information from the public, the medical community, and even its own advisers. In your view, what changes would be necessary to ensure greater transparency and accountability in the FDA’s decision-making process?

The agency understandably keeps certain information private to protect a company’s proprietary interests in an experimental drug. But I think greater transparency in the agency’s work can help the public gain confidence in its decisions. The Aduhelm debacle, which was the subject of a congressional investigation and is detailed in Doctored is an important case in point. The simufilam case shows how FDA secrecy and complacency can lead to the exploitation of patients who were taking a drug that was based on apparently false and doctored studies.
The agency could gain credibility by tightening rules on the “revolving door” problem – in which officials oversee the approvals of drugs, then leave the agency to earn much higher salaries at the pharma companies they previously regulated. It would also be beneficial for Congress to appropriate more funds for FDA, so that it’s approval process did not depend on fees from the companies whose drugs it examines – an inherent conflict of interest.

How should institutions respond to ensure greater integrity in research?

My book cites serious deficiencies in the way funders, regulators, universities, and scholarly journals have addressed the problem of image doctoring and misconduct generally in Alzheimer’s disease and more broadly. I believe that those institutional authorities have a responsibility to do much better for the sake of improving the scientific record and speeding the development of effective treatments. Patients, taxpayers, scientists, and doctors all have the right to demand that those authorities and gatekeepers of knowledge provide better stewardship of the scientific enterprise.

Drugs like lecanemab have shown statistically significant efficacy in slowing cognitive decline, but you point out that the clinical benefit may be imperceptible to patients and their families. What are the main risks associated with these treatments, and what ethical questions should physicians consider before prescribing them?

I’m not a doctor and don’t give medical advice. However, I know that many doctors properly try to help patients weigh the known risks of the drugs – including brain swelling and bleeding that infrequently cause death, and brain atrophy that occurs more rapidly than atrophy caused by the disease itself – against their possible benefits. As you note, those benefits are modest at best, and many neurologists and neuroscientists say they might be imperceptible to patients and loved ones. I think that many doctors explain, as they should, that the drugs don’t arrest or reverse the cognitive symptoms of the disease.
Since the publication of your book, have you received any feedback from the scientific community? Have any researchers acknowledged structural issues in the funding and publication system of Alzheimer’s research?
It’s been gratifying that most of my feedback from the scientific community, from physicians, and from patients or their loved ones has been overwhelmingly positive and appreciative. (This has also been reflected in the many reviews in the popular and scientific media, and in other coverage, which you can find links to on my website.) There have been some critical comments in the social media and a couple of critical articles written by a scientists who object to the book’s overall tone and descriptions. Those articles have taken a classic “strawman” approach: They falsely describe the book, then attack their own false descriptions.
The critics are almost entirely people whose careers have been based on exploring and verifying the amyloid hypothesis. Many of them have been and currently are deeply dependent on anti-amyloid drug makers for research funding, and many have taken large fees for consulting with those companies. I think that most reasonable people would say that those professional and financial conflicts of interest provide motivation for criticizing my work.

In conclusion, what is the role of investigative journalism in science, and what risks does it face in the current political climate?

A few scientists have criticized my book – which was completed last fall, long before Trump took office – because some of my ideas have been borrowed by high officials in the Trump administration for their own political purposes. Journalists have no control over what use or misuse others might make of their reporting. That should never be a reason to stop practicing journalism, especially when it comes to exposing fraud and misconduct that can affect millions of people.
I strongly object to the Trump administration’s slash-and-burn approach to American science, especially it’s unilateral funding and staffing cuts to NIH and universities. Anyone who loves science and respects the vital role of scientific research for humanity – as I do – should deplore those destructive actions.
In part due to their understandable fear about the future of science in today’s political climate, some advocates of the amyloid hypothesis have even called my book “disinformation” and “anti-science.” It is disappointing to hear a few well-known scientists suggest that open discussion of fraud and research integrity is more of a threat to Alzheimer’s research than the fraud itself. Particularly in today’s media and political environment, such complacency and condescension seems particularly misguided in an argument imploring the public to trust those self-described “true experts”.