Thursday, December 7

Possible fraud in important Alzheimer’s research: what are its implications?

What happened?

A publication in the magazine Science has uncovered a possible case of fraud in an important line of research against Alzheimer’s. The alarm signal was sounded by Matthew Schrag, a neurologist and neuroscientist at Vanderbilt University, and the magazine itself continued the analysis. Specifically, they identified that there were all kinds of image manipulations in at least ten articles on the so-called Aβ*56 peptide. All of them included the signature of the neuroscientist Sylvain Lesné.

Aβ*56 is a form in which beta-amyloid protein can be present, the substance that is found forming plaques in the brains of Alzheimer’s patients and that, according to the dominant theory in recent decades, is responsible for start the disease.

One of those ten articles is one of the most cited in the history of Alzheimer’s research. Published 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 criticism, 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 tried unsuccessfully to reproduce the results, but very few reported it. Although an irreproducible result does not necessarily imply fraud, the article acknowledges that there is little interest in negative results and it is difficult to contradict authoritative researchers.

Following the post, some items Y multiple comments In social networks they affirmed that all the research on Alzheimer’s was based on a fraud and that hundreds of millions of euros and decades of efforts had been wasted. However, many experts have tried to refute these conclusions and to put their repercussions into context. Everything revolves around the beta-amyloid protein.

What is β-amyloid

They 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 presumably toxic form but it is not found as part of the plaques.

This is a simple timeline of some important findings:

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

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

No. In the words of the Alzheimer’s researcher on Twitter Karl Herup, “The magnitude of the fraud is shocking, but the importance to the field of Alzheimer’s has been grossly exaggerated.” According to chemist Derek Lowe, a former Alzheimer’s researcher and responsible for a blog in the magazine Science, “It certainly increased the enthusiasm and funding levels in the area and gave people more reason to believe.” However, the work on Aβ*56 now in question “did not lead directly to any clinical trials on that particular form.” Too many eggs were probably put in the same amyloid basket, but it wasn’t caused by those items.

These works were a boost, but they are only a branch in the whole tree of theory. Also on Twitter, the researcher Samuel Marsh explained that “the main work in question did not establish the model of the amyloid plaque. He was talking about a specific oligomer called AB*56. There are many other articles in this field that show the importance and effects of oligomers and plaques.” And he continued: “I honestly doubt that the absence of this particular article and AB*56 from the historical scientific record would have significantly changed the last 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.”

For John Hardy, discoverer of one of the mutations that inevitably lead to the disease, “it is a shame that these works involve deception, and journals and institutions must take action against fraud when it is discovered.” However, “I have never thought that this article was important, and I think I have never referred to it in my own work.”

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

In recent years there has been an 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 symptoms may not be enough to develop the disease. On the other hand, and this is the main reason, although clinical trials designed to reduce plaques have repeatedly succeeded in reducing them, they have invariably failed to improve symptoms. Even those trials carried out early and in people carrying mutations that make them in the future develop the disease have not been shown no improvement.

There is currently only one approved anti-amyloid drug for Alzheimer’s, aducanumab. It was given the green light in the United States in the midst of 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 sufficiently safe.

What could explain the failure of clinical trials

Some of the explanations that are considered are these:

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

And it is becoming more and more accepted that Alzheimer’s disease is a syndrome, rather than an unequivocal disease, and that there are many factors to take into account.

On this particular case, this is how his explanation ended Samuel Marsh: “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. This is great news in and of itself, but hyperbolic and inaccurate information makes things worse.”