The well-known academic journal “Science” recently revealed that the pictures of a key paper on Alzheimer’s disease published in another well-known journal “Nature” in 2006 were suspected of being fake, and the experimental results of the paper were tampered with. If it turns out to be true, it means that 16 years of research and funding in this field have been directed in the wrong direction.
Since this paper directly proves an important hypothesis in Alzheimer’s disease research, it has been cited more than 2,300 times to date.
And its direct beneficiary, the first author, has since received huge support: $774,000 in funding over 4 years, and $7 million in grants.
As soon as the news came out, there was an instant uproar.
The core paper involved this time was published in Nature in 2006.
The paper proposes that a specific β-amyloid oligomer, Aβ*56, impairs brain memory and may be a key substance in inducing Alzheimer’s disease.
The researchers said they found the substance in transgenic mice, extracted it, purified it, and injected it into young healthy mice. The results showed that the mice had a decline in memory function.
That year, the discovery of this substance provided strong evidence for the amyloid hypothesis.
The hypothesis proposes that, in the brains of Alzheimer’s patients, oligomers formed after amyloid (Aβ) aggregates will form plaques, leading to neurofibrillary tangles, neuronal loss, and so on.
However, judging from the current investigation results, the * key result map of the Aβ56 experimental results in this paper is suspected of major fraud – almost identical bands appear in the experimental results.
For the part circled by the red box in the figure, the investigators calculated the strength of the relationship between the merged bands of the two lines, and the results showed that the correlation was 0.98 (1 means complete agreement), “almost unlikely to be a naturally occurring event”.
In the paper, the authors demonstrate through this result map that as the age of Alzheimer’s mice increases, the level of Aβ*56 in the body also increases.
Molecular biologist Elisabeth Bik said that it may be that the authors did not get the expected results in the initial experiment, so the data were tampered with to be more in line with the hypothesis. This further deepens the academic community’s suspicion of Aβ*56.
You know, in the past ten years, many experts have questioned the authenticity of the research on purified Aβ*56.
Donna Wilcock, an expert in Alzheimer’s disease at the University of Kentucky in the United States, said that the nature of this oligomer is very unstable and will spontaneously convert into other types of oligomers, and the purified sample is likely to be a mixture. This makes it impossible to attribute the symptoms of memory loss to Aβ*56.
Previously, the academic community even doubted whether Aβ*56 really existed. Many laboratories have tried to extract Aβ*56 before, but with little success.
In 2008, Dennis Selkoe, a proponent of the amyloid hypothesis and a well-known Alzheimer’s doctor, also mentioned in two papers that he did not find Aβ*56 in the human body.
Now that it is Science’s turn to come forward, not only is the experimental results impossible to reproduce, but also this “shoulders of giants” may no longer exist.
16 years of potentially misleading global research
As mentioned earlier, this “pioneering work” directly verifies the amyloid hypothesis. Since then, academia and industry have begun to bet heavily on this.
According to Science, at that time NIH (US Institutes of Health) support for “amyloid, oligomers and Alzheimer’s disease” rose from 0 to $287 million last year.
And this year, the NIH spent about $1.6 billion on the amyloid program. This amount directly accounts for half of the total funding for Alzheimer’s research.
This does not include the ideas and reflections that scientists have contributed to this field. Over the past decade, researchers have tried to reduce amyloid to treat Alzheimer’s disease. But their attempts failed: treatments that proved effective in animal models were ineffective in human patients.
For Nobel Prize-winning Stanford neuroscientist Thomas Südhof, this is the most immediate and obvious damage.
This fraud took the field of Alzheimer’s research back to 10 years ago, and academics were again divided into neuroimmunity hypothesis, inflammation hypothesis and amyloidosis hypothesis.
For the industry, many pharmaceutical companies have developed drugs based on this hypothesis. You must know that new drug research and development costs are high and the cycle is long. If the drug cannot be proven effective, all processes are meaningless.
It is worth mentioning that the initiator of this investigation stemmed from a question about drug research.
Matthew Schrag of Vanderbilt University, who was notorious for criticizing an FDA-approved anti-Aβ drug, found a like-minded attorney.
The lawyer is investigating Simufilam, a drug in clinical trials that the developer claims can improve cognition by repairing a protein that blocks Aβ deposition. And they suspected that the research behind it was fraudulent, so they launched an investigation using existing medical knowledge.
However, some netizens believe that the fraud does not have much impact. The industry currently recognizes the relationship between Aβ*42 and Alzheimer’s disease.
Harvard neuroscientists said that although the results of Aβ*56 are questionable, he hopes that everyone will not give up the amyloid hypothesis completely. However, he also mentioned that if several clinical drug experiments have failed now, this hypothesis may be hidden.
At present, Nature has issued a statement and began to investigate the paper. A spokesman for the University of Minnesota, where the research team belongs, said the school is also reviewing the matter.
It is worth mentioning that after Sylvain Lesné, the first author of the thesis, was exposed, about 20 articles were found to be suspected of falsification at the same time. 10 of them are related to Aβ*56. The results of the investigation show that at least 12 of the experimental results pictures in these papers are suspected of major fraud.
Dennis Selke, a well-known doctor in the field of Alzheimer’s disease, said bluntly: “I don’t think (the pictures) have any other reasonable explanation other than human manipulation.”
At the same time, some scholars also revealed that in a past collaboration with Sylvain Lesné, they found that the images he provided were very suspicious, so they asked students to reproduce the experiment, but they all failed in the end. Afterwards, he questioned Sylvain, who firmly denied it.
Ultimately, the co-authored paper was withdrawn before publication, and the academic broke ties with Sylvain.
Corresponding author: I still have confidence in Aβ*56
According to Science, the corresponding author of the paper, Chinese scientist Karen Ashe, declined to be interviewed. But she said in her reply email that she still has confidence in Aβ*56, and said that she is still studying the related content of Aβ oligomer structure.
At the same time, she believes Science’s investigation has exaggerated and misrepresented the paper’s impact on academia. “I have spent decades studying Alzheimer’s disease, only to find out that a colleague of mine has tampered with the image and misled me and the entire academic community.” “It is even more distressing that such a prestigious scientific journal , and blatantly distorted my research results.”
Asia is a professor of neurology at the University of Minnesota School of Medicine and director of the school’s Alzheimer’s Research Laboratory.
In fact, because of this research, Asia won many awards in the field of Alzheimer’s disease. She won the $100,000 Potamkin Prize just two weeks after the paper was published. He also received the MetLife Foundation Alzheimer’s Medical Research Award, which provides a $50,000 award + a $200,000 research grant.
It is reported that Asia has received more than $28 million in funding from the National Institutes of Health (NIH).
On the other hand, Sylvain Lesné, the first author of the paper, also became famous for this achievement.
In 2009, he established a laboratory funded by the NIH at the University of Minnesota. Between 2008 and 2012, he received more than $770,000 in funding from the NHS to study Aβ*56, and more than $7 million to study Alzheimer’s-related issues. In 2020, he also became the leader of the Neuroscience Graduate Program at the University of Minnesota.
At present, Sylvain has not made any response to the outside world, and the relevant investigation is continuing.
Reference link:
[1]https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease
[2]https://www.startribune.com/senior-university-of-minnesota-scientist-responds-to-fraud-allegations-in-alzheimers-research/600192351/?refresh=true
[3]https://www.zhihu.com/question/544750364
