Possible Fraud in Important Alzheimer’s Disease Research: What Are Its Implications?

What happened?

A publication in the magazine Science uncovered a possible case of fraud in an important line of Alzheimer’s disease research. The wake-up call came from Matthew Schrag, a neurologist and neuroscientist at Vanderbilt University, and the magazine itself continued the analysis. Specifically, they identified that there were all manner of image manipulations in at least ten papers on the so-called Aβ*56 peptide. All of them bore the signature of neuroscientist Sylvain Lesné.

Aβ*56 is one form in which the beta-amyloid protein may be present, the substance that forms plaques in the brains of patients with Alzheimer’s disease and which, according to the dominant theory of recent decades, is responsible for the onset of the disease.

One of these ten articles is one of the most cited in the history of Alzheimer’s disease research. Posted in the magazine Nature in 2006, claimed that when the Aβ*56 form was injected into healthy rats, they developed memory loss. It was the first time that a substance theoretically present in the brains of people with Alzheimer’s had been shown to directly cause these symptoms. It was a boost to the amyloid hypothesis.

Schrag avoids the term “fraud” in his review, describing his findings as a “red flag”. Other experts consulted by the magazine Science they describe them as “striking examples of image manipulation”. It is also said that many other groups have tried unsuccessfully to replicate the results, but very few have reported it. Although a non-reproducible result does not necessarily imply fraud, the article acknowledges that negative results generate little interest and that it is difficult to contradict authoritative researchers.

Following the post, some items there several comments In social networks, they claimed that all research on Alzheimer’s disease was based on fraud and that hundreds of millions of euros and decades of effort had been wasted. However, many experts have attempted to refute these findings and put their implications into context. It’s all about the beta-amyloid protein.

What is β-amyloid

These are small fragments that come from the so-called amyloid precursor protein. There are many different forms that tend to aggregate and eventually form the characteristic plaques of Alzheimer’s disease. In the case of Aβ*56, it would be what is called a soluble oligomer, it would be a likely toxic form but it is not found in the plaques.

This is a simple timeline of some important discoveries:

  1. Between 1906 and 1911, Alois Alzheimer (and Oskar Fischer) began to describe patients’ characteristic plaques.
  2. In 1984, it was established that the β-amyloid protein is the main component plates.
  3. in 1991 start to be published that several mutations that increase the amount of amyloid precursor protein inevitably cause disease in those who carry them. It is assumed to be the cause of Alzheimer’s disease and the theory is becoming mainstream.

Does the possible fraud dismantle the theory of amyloid and Alzheimer’s disease?

No. In the words of the Alzheimer’s researcher on Twitter Karl Herrup, “The scale of the fraud is shocking, but the significance to the field of Alzheimer’s disease has been grossly exaggerated.” According to chemist Derek Lowe, a former Alzheimer’s disease researcher and head of a blog in magazine Science, “It has certainly increased enthusiasm and funding levels in the region and given people more reason to believe.” However, the work on Aβ*56 now in question “did not lead directly to any clinical trials on this particular form”. Too many eggs were probably put in the same amyloid basket, but it was not caused by these elements.

These works were a boost, but they are only a branch in the whole tree of the theory. Still on Twitter, the researcher Samuel Marais explained that “the main work in question did not establish the model of amyloid plaque. He was talking about a specific oligomer called AB*56. There are many other articles in this area that show the importance and effects of oligomers and plaques. He continued, “Frankly, I doubt that the absence of this particular paper and AB*56 from the historical scientific record has significantly altered the past 20 years of drug development for Alzheimer’s disease. This is because there is strong genetic and other evidence for the role of amyloid in the disease.”

By John Hardy, discoverer of one of the mutations that inevitably lead to disease, “it is unfortunate that this work involves deception, and journals and institutions must act against fraud when it is discovered.” However, “I never thought this article was important, and I don’t think I’ve ever referred to it in my own work.”

The amyloid theory was already controversial before this case. Because?

In recent years, there has been intense debate about the relevance of amyloid in Alzheimer’s disease. One reason is that many older people have amyloid plaques but no symptoms, so the symptoms may not be enough to develop the disease. On the other hand, and this is the main reason, although clinical trials aimed at reducing plaques have repeatedly succeeded in reducing them, they have invariably failed to improve symptoms. Even these early and in people with mutations that cause them to develop the disease in the future have not been demonstrated no improvement.

There is currently only one anti-amyloid drug approved for Alzheimer’s disease, aducanumab. It was given the green light in the United States amid a huge controversy, both because of the strange development of clinical trials and because of the final decision. In Europe, the European Medicines Agency refused to approve italluding to the fact that it had not shown clinical benefit and was not safe enough.

What could explain the failure of clinical trials

Some of the explanations considered are:

  • Although logically and genetically this is difficult to accept, it is possible that amyloid is what is called an epiphenomenon, something that accompanies the true cause but does not act as such.
  • The treatments included in the trials may not arrive in time. The damage produced by amyloid may be very early, and reducing it once it has triggered the aggression may not be enough. Although some trials have been carried out on people still without symptoms, it may still be too late.
  • Another option is that the antibodies used to reduce amyloid were not reducing it enough, or they were working against certain forms of amyloid that were the most toxic. In this case, the total amount would be reduced, but not what actually causes the damage.

And there is growing recognition that Alzheimer’s disease is a syndrome, rather than an unequivocal disease, and that there are many factors to consider.

On this particular case, here is how his explanation ended Samuel Marais“Okay, that’s all for now. Horrible behavior, yes. The reason the Alzheimer’s disease field has focused on amyloid for the past 16 years: Absolutely not. That’s great news in itself, but hyperbolic and inaccurate information makes matters worse.

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