A big lie?
Is everything we knew about Alzheimer's disease untrue? Falsifications found in scientific articles
Matthew Schrag, a neuroscientist and physician from Vanderbilt University (Tennessee, USA) discovered fake images in dozens of articles about Alzheimer's disease, which casts doubt on the basic theory of its occurrence.
In August 2021, he was involved as an expert in the lawyer's investigation into the case of Cassava Sciences, which developed the experimental drug "Simufilam" (Simufilam). The manufacturer claimed that the drug improves cognitive functions in the brain, which presumably causes Alzheimer's disease. The company was suspected that individual studies related to Simufilam could be "fraudulent", and volunteers participating in drug trials could receive serious harm to their health.
Studying the published data on the effectiveness of the drug, Schrag came across implausible images (visual data of tests for the presence of Aß — beta-amyloids, which presumably provoke dementia. — Approx. "AIDS.CENTER") in dozens of scientific articles devoted to research on Alzheimer's disease and a variety of related experiments.
What kind of research are we talking about?
In 2006, the journal Nature published a convincing article by physician and neuroscientist Karen Ash from the University of Southern California about the cause of Alzheimer's disease. Despite the fact that a team of scientists worked on the study, the main author of the article was named neuroscientist Sylvain Lesnet from the University of Minnesota (UMN), a young scientist whom Ash hired immediately after completing his postgraduate studies at the University of Caen-Normandy in France. In collaboration with Karen Ash, Lesne prepared all the images for publication.
Ash had the perfect reputation: She participated in the pioneering work of Nobel laureate Stanley Prusiner on the study of prions — infectious proteins that cause rare neurological disorders. In the mid-1990s, Ash created a transgenic mouse whose brain produced the same Aß as in humans, and also formed plaques that disrupted brain function. The mouse became a "demonstration model" of Alzheimer's disease.
Together with a group of scientists in 2006, Ash isolated a previously unknown type of Aß from the brains of transgenic mice — the Aß*56 oligomer — with a relatively large molecular weight compared to other oligomers. It was injected into the brain of ordinary young rats, after that their ability to remember simple, previously learned information, such as the location of a hidden platform in a maze, dropped sharply.
This experience confirmed the dominant at that time, but extremely contradictory amyloid hypothesis of Alzheimer's disease. According to her, it is the accumulation of Aß in brain tissues that causes a devastating disease that affects tens of millions of people around the world. After the publication of Lesne and Ash's article in the journal Nature, scientists focused on creating a drug that slows down the production of Aß in the body.
The article in Nature has been cited in about 2,300 scientific publications — more than all the others, according to the Web of Science database. Since then, annual support for amyloid and oligomer research in Alzheimer's disease has grown from almost zero to $287 million in 2021. In 2022, the US National Institutes of Health spent about $1.6 billion on similar projects. This is about half of the total funding for the fight against Alzheimer's disease. While all funding was spent on amyloid research, all other studies of other potential causes of the disease were sidelined. Scientists believed that it was Lesna and Ash who helped to cause this excitement and create the "amyloid mafia".
Lesne and his colleagues were able to convince the scientific community that it is Aß*56 that causes dementia in laboratory rats. Subsequently, this oligomer was named the "star suspect" in Alzheimer's disease.
"It was a really big discovery that turned the whole field upside down partly because of Ash's impeccable credibility," says Donna Wilcock, an Alzheimer's specialist at the University of Kentucky. "This has prompted many other researchers to look for these [heavier] oligomers."
But even before Schrag's study, the evidence that Aß*56 plays a key role in the development of Alzheimer's disease was puzzling to many scientists. Such oligomers are unstable, spontaneously turn into other types of oligomers. Even after purification, several different types may be present in the sample, so it is difficult to say that cognitive impairment is caused only by Aß*56. Several laboratories have tried to isolate Aß*56 and failed, but only a few of them have published their results.
The results of hundreds of clinical trials of therapy directed against Aß were inconclusive. In two papers in 2008, the doctor Dennis Selkow from Harvard University stated that he could not find Aß*56 in human fluids or tissues.
All subsequent drug developments continued to rely on the fight against Aß, thanks to the authority of the article in Nature. The drug Aduhelm was even developed, which caused a lot of controversy, including criticizing it Matthew Schrag. However, its use has been approved by the FDA.
How did Matthew Schrag identify scientific falsification?
In December 2021, Schrag visited PubPeer, a website where scientists note possible errors in published works. When searching for "Alzheimer's disease", he was struck by reports of articles in The Journal of Neuroscience. They questioned the authenticity of the images used to differentiate Aß and similar proteins in mouse brain tissues. The images had rows of stripes reflecting the presence of certain proteins. Several fragments of these bands turned out to be duplicated. Schrag found similar problems with other images in the same articles, about which there were no previous posts on PubPeer. Fragments of an image showing an increase in the level of Aß*56 in old mice as Alzheimer's symptoms appeared were copied and glued together, which made the level of Aß*56 look higher than it could actually be.
Schrag quickly discovered other Lesne articles that attracted PubPeer's attention, and later decided to check all of his publications. Eventually, he came across a seminal article in Nature that formed the basis of many other studies. As it turned out, it also contained fake data. Schrag noted a lot of duplicated images and some markings indicating cut and pasted fragments. Independent analysts have admitted that some of the alleged manipulations may be digital artifacts that accidentally occur during image processing. Moreover, they revealed many other questionable spots and backgrounds that Schrag missed.
In total, Schrag and independent researchers identified more than 20 suspicious Lesne works, ten of them related to Aß*56.
Lesne declined to comment. Ash also did not answer the questions, writing "I still believe in Aß*56" and noting her current work on studying the structure of Aß oligomers. "We have promising first results. I remain encouraged by this work and believe it is able to explain why anti-Aß therapy can still work despite recent failures with amyloid plaques."
Some scientists, who previously referred to the Nature article in their works, recognized Schrag's investigation of manipulation as convincing. For example, Dennis Selkow, who quoted the ill-fated article at least 13 times, agreed that manipulations are indeed possible in the images. This is more than enough to cast doubt on the entire work, Selkow believes, and calls the obviously falsified corrections "shocking." "In science, as soon as you publish your data, which cannot be easily reproduced, there is a fear that they are incorrect or do not correspond to reality. There is very little clear evidence that Aß*56 exists and reproducibly correlates with signs of Alzheimer's disease — even in animal models," he says.
Science Magazine, which published Schrag's investigation, contacted Ash for an explanation. She separately published material on PubPeer in defense of some of the images that Schrag disputed in the Nature article, and provided fragments of several original, unpublished versions that have no obvious traces of digital cropping. However, they reveal something that Schrag and Selkow consider even more criminal: several strips were copied and pasted from neighboring areas.
"The authors seem to have made drawings by combining parts of photographs from different experiments,— says Elizabeth Bick, a molecular biologist and renowned consultant in forensic imaging. "The experimental results obtained could be far from the desired ones, and these data were changed to better match the hypothesis."
While federal agencies, universities and journals were quietly investigating the incident, Schrag decided to speed up the process by submitting his findings to the journal Science, even knowing that this could jeopardize his own grants and further publications. But he says he feels an urgent need to publicize work that could mislead specialists and slow down the race to save lives. "You can cheat to get an article. 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 about that."
Some scientists now suspect that Lesne's work has been conducting research in the wrong direction for 16 years. "The immediate and obvious damage is wasted funding from the US National Institutes of Health and wasted thinking in this area, because people used these results as a starting point for their own experiments," says Stanford University neuroscientist Thomas Sudhof, Nobel laureate and expert on Alzheimer's disease.
In 2020, he became the head of the University of Minnesota's graduate program in neuroscience, and in May 2022, four months after Schrag exposed the forgery, Lesne even received a grant from the agency with support for five years.
Questions about Lesna's work are not new. Cell biologist Denis Vivien, a senior researcher at the University of Caen-Normandy, was a co-author of five Lesne papers. They worked together on an article for the journal Nature Neuroscience on Aß. During the final editing, Vivien saw images of immuno—coloring provided by Lesna - when antibodies detect proteins in tissue samples. They seemed doubtful, and he asked the students to repeat the results. Their attempts were unsuccessful. Vivien says that he met with Lesne, but he denied his guilt. Although Vivien did not have irrefutable evidence of wrongdoing, he withdrew the article before publication and severed all contacts with Lesne.
Work that can mislead an entire field of research
A few days after the Science request, Nature magazine published a note saying that it was investigating Lesne's 2006 paper and advised caution about its results. The Journal of Neuroscience also published five suspicious Lesne articles, the authenticity of which has yet to be determined. A representative of the Journal of Neuroscience said that he would be guided by the recommendations for evaluating publications The Committee on Publication Ethics, but otherwise did not give any comments.
Like other efforts to combat Aß, studies of toxic oligomers have not led to effective treatments. "Many companies have invested millions or even billions of dollars in the fight against soluble [oligomers] Aß. And it didn't work," says Daniel Alcon, president of the bioscientific company Synaptogenix, who once led neurological research at the NIH.
Selkow adds that the amyloid hypothesis of the development of Alzheimer's disease remains viable. "I hope that people will not lose heart because of this blatant example of unfair work in the field of Aß-oligomers," he believes. But if the current phase three clinical trials of three drugs targeting amyloid oligomers fail, then the hypothesis will be in jeopardy.
The Lesne episode may further undermine public confidence in science at a time of growing skepticism and attacks. But scientists must show that they can find and correct rare cases of a clear violation. "We need to announce these examples and warn the world," says Salkow.
Charles Piller, Science
Translated by Tatiana Marinovich
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