The Worst Paper in History: Two decades and billions of dollars wasted on deliberate fraud

That fraudulent Alzheimer’s Paper

Mice are used for Alzheimer’s research

I come down hard on STEM culture, but this is worse than I ever imagined

Publish or Perish Does Not Help Earn Scientific Trust

Unfortunately, distrust in science currently is very high. Many scientists are highly dedicated to advancing their field, with the most noble of intentions. Scientific papers do go through rigorous peer-review process to attain a high quality of writing, data analysis, experimental design, and conclusions. However, a paper is just a paper. Science has labored under the myth that “lone” scientist or “single” discoveries are the end all be all.

In reality, we often have to read dozens or even hundreds of papers on a given research topic to really understand it thoroughly. Over time, multiple studies on a research topic can be reviewed, evaluated for consistency, and larger conclusions are drawn which often shape research directions. We should never solely rely on the outcome of a single scientific paper.

Furthermore, peer-review can only do so much. The process is haphazard; professors are cold emailed by editors asking if they want to review a paper. The reviewer usually has no formal instruction, just evaluates the paper, and returns it. They are unpaid so there is literally no incentive for them to go above and beyond in reviewing. Plus, they cannot replicate the experiment or re-run calculations. The journal editor has to trust the authors.

The “publish or perish” mentality can compromise scientific integrity. There is less prestige associated with studies which validate previous work or are “negative’ results (do not contain significant outcome). Producing novel research is highly rewarded in academic publishing and careers. This is very dangerous.

The Infamous Alzheimer’s Paper

Lesné, S., Koh, M., Kotilinek, L. et al. RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006). https://doi.org/10.1038/nature04533

In 2022, a highly cited 2006 paper entitled “A specific amyloid-β protein assembly in the brain impairs memory.” (Nature) was found to have had fraudulent data and tampered images. Hundreds of millions of National Institutes of Health (NIH) dollars went to funding project proposals that were based on this paper’s results.

The paper was famous for suggesting that a certain amyloid beta protein (Aβ*56) could cause Alzheimer’s. The authors reported that injecting this protein into rats could cause memory issues, and that the protein was found in “genetically engineered” mice with Alzheimer’s. This was considered to be a huge breakthrough in the field. Because once a cause is found, they could start working on a cure.

Because this paper supposedly pinpointed a specific protein which could theoretically be targeted therapeutically, research funding rose sharply. Thus, for decades researchers tried to develop medications (“anti-Aβ drugs”) that reduced or blocked this protein production from the brain. Unsurprisingly, the experimental drugs all failed. When the fraudulence was discovered, the Food and Drug Administration (FDA) initially refused to halt clinical trials of drugs that were based on the science from this paper. These clinical trials gave participants false hope, wasted resources, and diverted money away from finding other causes and treatments.

This fraud is particularly devastating given the human element involved. Over 7 million Americans are living with Alzheimer’s and there is no cure. It’s clear that the scientific community was willing to jump on the bandwagon of optimism and wish-fulfillment. They wanted it to work. Everyone wanted it to be true.

By 2006, the field of Alzheimer’s research had reached an impasse regarding the “amyloid hypothesis”. German physician Alois Alzheimer first began researching Alzheimer’s in 1906; he linked “plaque” (amyloid) in the brain to the disease. As life expectancies increased in the 20th century, so did Alzheimer’s. The “amyloid hypothesis” that the accumulation of amyloid in the brain is the driver of the disease was the prevailing idea in the late 1990s and early 2000s. However, failed clinical trial after failed clinical trial undermined this hypothesis. So, when the 2006 study in Nature study was published, it ushered in a new era of optimism.

How the Fraud was Discovered

Neuroscientist and Physician, Matthew Schrag, had gained notoriety for publicly criticizing FDA approval of the anti-Aβ drugs related to Alzheimer’s. Simufilam was developed by Cassava Sciences, which claimed the drug could block the production of the “sticky” brain deposits of protein amyloid beta, and thus improve patient cognition. Schrag was contacted in August of 2021, by someone investigating the possibility of fraudulent research related to Simufilam development.

Schrag’s own research contradicted the efficacy of anti-Aβ drugs and he feared that patients in clinical trials would face adverse side effects with no improvement in cognition. Schrag was paid by these attorneys to investigate the underlying science behind anti-Aβ drugs. During this time, he found several altered or duplicated images among the trail of journal articles leading back to Lesné et al. 2006. Schrag’s findings were reported to the FDA and NIH. Apparently, the authors had pieced together photos from various different experiments to fit their hypothesis.

Meanwhile, Science, conducted a 6-month investigation which supported Schrag’s suspicions. Not only did they find tampered images in Lesné et al. 2006, but at least 70 other papers produced from authors of the study. After some time, Schrag decided to go public, arguing that “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,” he says. “Biology doesn’t care.”

Charles Piller’s Science article “Blots on a field?” was published on 21 Jul 2022, rocking the scientific community.

The Power and Prestige of Biomedical Research

Karen Ashe of the University of Minnesota (UMN) is credited with the development of a transgenic mouse that can form human Aβ in its brain and can serve as an Alzheimer’s model. In these mice’s brains, Ashe’s team discovered Aβ*56. Ashe became famous in the Alzheimer’s research community. Her website proclaimed that this protein was “the first substance ever identified in brain tissue in Alzheimer’s research that has been shown to cause memory impairment.” Ashe won the Potamkin Prize for neuroscience. The paper had over 2300 citations and annual NIH support for studies labeled “amyloid, oligomer, and Alzheimer’s” went from near zero to $287 million in 2021.

Neuroscientist Sylvain Lesné was hired by Ashe straight from his Ph.D. program (University of Caen Normandy, France). His work was the “smoking gun” for the Aβ-hypothesis in the brain—by injecting Aβ*56 protein into rats they supposedly exhibited dementia-like symptoms. Given current evidence, Lesné’s results were merely an elaborate mirage.

The other authors included Ming Teng Koh, Linda Kotilinek, Rakez Kayed, Charles G. Glabe, and Michela Gallgher who all are still publishing on Alzheimer’s research; they seemingly have not publicly spoken out about their roles in the manuscript.

However, co-author Austin Yang became a NIH program officer, who awarded Lesné (who had already gotten at least $8 million from NIH since 2008) a grant 4 months after the NIH had been notified of research integrity issues. To date, none of the authors apologized or took responsibility for their role on the paper.

None of them have faced criminal indictment for the millions of dollars they obtained from federal funding agencies based on fabricated data.

The “amyloid mafia”

The biggest contradiction in the amyloid Alzheimer’s hypothesis is that amyloid deposits have been found in people without Alzheimer’s. Given improvements in molecular methods in the last two decades, there is also far more complexity in amyloid proteins than was previously thought.

Even before Schrag, Lesné et al. 2006 had been flagged for possible errors on PubPeer (a website that critiques published works). Despite the deluge of amyloid-related research, virtually nobody has since detected Aβ*56, and almost no other research groups were able to directly confirm Lesné et al. 2006’s findings.

However, this amyloid hypothesis gained power and prestige in the field for almost two decades. The NIH spent about $1.6 billion on projects that mention amyloids in 2021-2022, about half of all Alzheimer’s funding. Scientists who had suggested other causes of Alzheimer’s (e.g., immune dysfunction, inflammation, viruses) were reportedly squashed by the “amyloid mafia.” They struggled to get funding, or their ideas advanced into drug development.

This collection of power and prestige in academic research science, also prevents young scholars from rising in the field. This ‘ecosystem’ of prestige makes it difficult for women and people of color to get hired as faculty members:

Ultimately, the inequalities inherent in this prestige hierarchy can hinder the flow of ideas and the formation of new fields […] Innovative ideas that originate within the relatively isolated networks of higher-prestige universities solidify within them before streaming down to academics affiliated with lower-prestige institutes.

The authors faced no criminal consequences

Hoau-Yan Wang and Marilyn Albert have been indicted for fraudulent data in grant applications related to Alzheimer’s research; Karen Ashe (still employed at UMN) and Sylvain E. Lesné (forced to resign from UNM).

It was not until 2024 that the paper was retracted at the request of nearly all the authors, though Lesné disagreed. The remaining authors conceded that images “appeared to have been doctored, although they still defend the validity of the findings.” Lesné is still publishing, though was forced to resign from UNM in 2025 when they found issues in his other manuscripts.

In 2024, The Minnesota Daily reported that while Ashe’s lab continues to research Alzheimer’s disease, Dongming Cai replaced Ashe as director of the N. Bud Grossman Center for Memory Research and Care. Ashe claims that their work was ‘mis-represented” by Piller’s “Blots on the Field”:

“He framed our work inaccurately, implying that our discovery of Abeta*56 had misled the field into developing therapeutic antibodies that didn’t work,” Ashe said. “Although the changes that were made to the figures were a misrepresentation and entirely unacceptable, they did not affect the main conclusions of the figures themselves or of the paper as a whole,”

Ashe suspected the image tampering was done by a lab member that left in 2008. This does not explain, further image tampering found in Lesné’s other work.

Criminal indictment for scientific fraud is rare but is not unprecedented. Scientific fraud had first been brought to trial in 2012. Marilyn Albert, a former professor of psychiatry at Harvard Medical School, and Massachusetts General Hospital (MGH), was accused of submitting a $15 million grant application based on data which has been manipulated into statistical significance to NIH, ironically also for Alzheimer’s research funding. The Defendents faced a $45 million penalty to the U.S. government under the False Claims Act in 2012. Apparently, Marilyn Albert is currently the Director of the Division of Cognitive Neuroscience at Johns Hopkins University and Director of the Johns Hopkins Alzheimer’s Disease Research Center.

Hoau-Yan Wang, a former professor at the City University of New York (CUNY), who contributed to the development of the drug anti- Aβ drug Simufilam, was actually indicted by the Department of Justice in June 2024 for defrauding the NIH of $16 million in grants. Cassava Sciences settled with the U.S. Securities and Exchange Commission but admitted no wrongdoing. Cassava Sciences executives made millions in salary and stock trades despite Simufilam’s failure.

Will Science Take Action?

Investigative Journalist Charles Piller recently released a book called “Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s”. Disturbingly, this review of his book seems to imply that fraud in biomedical sciences is more prevalent than we ever thought. Piller documented how regulatory agencies, bespoken to industry interests, consistently failed to protect public health, and that the FDA, despite contrary recommendations by experts, repeatedly approved anti-Aβ drugs while dismissing legitimate concerns. Cassava Biosciences’ clinical trials actually were allowed to proceed despite the misconduct investigation and a Citizen’s Petition calling for their suspension. Piller recently wrote to the New York Times that

“Over the past 25 years, Alzheimer’s research has suffered a litany of ostensible fraud and other misconduct by world-famous researchers and obscure scientists alike, all trying to ascend in a brutally competitive field. [..] These deceptions have warped the trajectory of Alzheimer’s research and drug development, prompting critical concerns about how bad actors, groupthink and perverse research incentives have undermined the pursuit of treatments and cures. It haunts me that this may have jeopardized the well-being of patients.”

(I wrote this article before this book came so I will have to check it out, it sounds like a great book).

Terrible Legacies:

• Wasted time, money, resources

• Gaslighting other scientists

• Losing almost 2 decades of other research avenues for curing Alzheimer’s

• Demonstrates the failure of peer-review and the “friendship/prestige” bonus—famous and well-connected authors are more likely to be published

• False hope and possible negative side-effects for clinical trial patients

• Fuelling the fire for public distrust of science

Changing Academic Publishing

• No for-profit academic journals. No open access fees. Academic journals make larger profit margins than Apple.

• Mandating data transparency, code, original images, data, published alongside the paper

• Developing data plan and manuscript outline ahead of time with statistical corrections ahead of time.

• Impact factor, citation counts should not be success metrics and should not be used in hiring decisions.

• Decent, livable salaries for academics.

• Academic journals training and paying peer-reviewers. All academic manuscripts must be evaluated by a statistician, and then two other field experts.