Falsified study challenges 15 years of research

It’s a thunderclap in the scientific community, in the field of Alzheimer’s research, as well as a kind of betrayal for all patients and their loved ones. 15 years of research would be based on a study, dating from 2006, whose conclusions would simply be fabricated. In the years that followed, the scientific community therefore tried to advance the theory advanced by this fraudulent study by the French neuroscientist Sylvain Lesné, based in the United States, namely that the accumulation of a by-product of amyloid plaques on neurons would be mainly responsible for Alzheimer’s. The consequence is a waste of time and public money for research and dashing hopes for patients. Further investigations are necessary. In any case, this study throws a stone in the weeds of research funding, sometimes more influenced by notoriety than by purely medical and human interest, and apparently unscrupulous.

In the early 2000s, several clinical trials aimed at identifying a drug capable of combating Alzheimer’s disease were launched. To date, all have unfortunately proven unsuccessful. We must be aware that Alzheimer’s is a chronic disease beginning several decades before the appearance of the first signs, affecting the most complex organ of the body, the brain.

Nevertheless, research on Alzheimer’s disease has made massive progress over the past 15 years. Many scientific advances have been made, which now make it possible to better understand and better diagnose Alzheimer’s disease, to better monitor its development and to identify new therapeutic targets. It is also thanks to these advances in research that it is possible to implement effective prevention in order to delay the appearance of the first signs of the disease.

Recently, the review Science published an investigation, led by Matthew Schrag (Vanderbilt University) concerning one of the most cited studies in the world of Alzheimer’s research, and on which rest many therapeutic hopes: the hypothesis of toxic by-products amyloid plaques present on the neurons, which would be the “main culprits” for the development of this pathology. The many dead ends of research for 15 years would be, according to the survey of Sciencemainly due to a hypothesis that turned out to be much less reliable than we thought.

From the manipulation of scientific images in the service of notoriety

The study in question is that of the French neuroscientist, based in the United States, Sylvain Lesné, published in 2006 under the aegis of the University of Minnesota. Moreover, the latter has just opened an investigation into the researcher, following these allegations.

It all started in August 2021, when a law firm contacted neurologist and neuroscientist Matthew Schrag to review work on Simufilam, an anti-Alzheimer’s drug developed by the American laboratory Cassava Sciences. This molecule would improve cognitive functions, in part by “repairing” a protein, filamin A, which can block cerebral deposits of beta-amyloid (Aβ) protein, a characteristic of Alzheimer’s disease. These lawyers were mandated by researchers, holders of Cassava Sciences shares, who feared fraud on this research and for which they have since filed a petition.

This is how Matthew Schrag began a careful examination of the study on which the design of this drug was based, that of Sylvain Lesné and the amyloid hypothesis. Then he expanded his corpus of suspicious studies and found manipulated images in dozens of articles involving Alzheimer’s disease.

The work of Lesné and his colleagues underlies a key element of the dominant but controversial amyloid hypothesis of Alzheimer’s disease, which holds that clusters of Aβ, called plaques, in brain tissue constitute one root causes of disease — specifically the byproducts of these plaques, called “toxic oligomers.” This is how they discovered an Aβ subtype (Ab*56) and they seemed to prove that it caused dementia in rats. If Schrag’s doubts are correct, Lesné’s findings are an elaborate mirage.

As Molecular Biologist and Forensic Imaging Consultant Elisabeth Bik explains, the authors ” seemed to have composed figures by putting together parts of photos from different experiences. The experimental results obtained might not have been the desired results, and these data could have been modified to… better correspond to a hypothesis “. But as Schrag recalls in the survey: “ You cannot cheat to cure an illness. Biology doesn’t care “.

To highlight manipulation of the results, Schrag analyzed images showing Ab*56 levels from the 2006 paper, increasing according to the study in older mice as symptoms appear. There he discovered eerily similar bands, which would have led to the toxic oligomer appearing more abundant than it actually was. Concretely, Schrag matched the level of contrast in the two sets of suspect bands, then made the backgrounds black to make the bands easier to see, and colorized them. Finally, he matched their size and orientation precisely: the superposition is perfect, too much so that there was no manipulation. Schrag shows an explicit counterexample to validate his conclusions, where the differences are, in this case, visible by superposition.

(A) Highlighting image manipulation. (B) Unmanipulated image, where the superposition of the two bands is not perfect. © Schrag/Science (modified by Laurie Henry for Trust My Science)

Incidentally, Dennis Selkoe of Harvard University, one of the leading proponents of the amyloid and toxic oligomer hypotheses, stated in two 2008 papers that he could not find Ab*56 in fluids. or human tissue. Selkoe reviewed Schrag’s file on Lesné’s articles, at the request of Science. He didn’t see any manipulation in every suspicious image, but says: ” There are definitely at least 12 or 15 images for which I agree there is no other explanation [que la manipulation] “. Many other images in Lesné’s articles could be inappropriate — which is more than enough to call into question the entire work, Selkoe adds.

Lesné did not respond to requests for comment or additional scientific information from Science.

A fraud that does not call everything into question, but questions the objectivity of funding

The immediate consequence is obviously the waste of resources in time and money. Nevertheless, it must be understood that even if the fraud is attested, all the work is not to be thrown away, even less the hypothesis on which this study was based.

Indeed, one of Alzheimer’s greatest mysteries is also its most distinctive feature: the plaques and other protein deposits that German pathologist Alois Alzheimer first saw in 1906 in the brain of a deceased patient. suffering from dementia. In 1984, Aβ was identified as the main component of plaques. And in 1991, researchers traced familial Alzheimer’s disease to mutations in the gene for a precursor protein from which amyloid is derived. According to many scientists, it seemed clear that the accumulation of Aβ triggers a cascade of damage and dysfunction in neurons, causing dementia. Slowing down amyloid deposits has therefore become the therapeutic strategy of choice.

By the early 2000s, “toxic oligomers,” subtypes of Abs that dissolve in certain body fluids, had become the likely primary culprit of Alzheimer’s disease, potentially more pathogenic than insoluble plaques. In 2006, the University of Minnesotoa team, including Lesné, discovered a previously unknown type of oligomer, dubbed Ab*56, due to its relatively high molecular weight compared to other oligomers, and responsible in large part, according to the authors, of the development of Alzheimer’s disease. This study revitalized research that had stalled and silenced the doubts that were beginning to arise in the face of these toxic oligomers derived from amyloid plaques.

However, hundreds of clinical trials of amyloid-targeted therapies have given few glimmers of hope; only the disappointing Aduhelm got FDA approval. Yet Aβ still dominates drug research and development. The NIH (National Institutes of Health) spent about $1.6 billion on projects that mention amyloids last year, about half of their overall funding for Alzheimer’s disease. Scientists who posit other potential causes of Alzheimer’s, such as immune dysfunction or inflammation, complain that they have been sidelined by the ” amyloid mafia “.

But objectively, the Ab*56 protein is not the only oligomer studied for Alzheimer’s. The fact that the results concerning this specific oligomer are potentially fraudulent does not imply that the others are also, much less that the amyloid hypothesis is false. On the other hand, the researchers now better understand why no one was able to replicate the results concerning this oligomer.

In conclusion, faced with such disabling pathologies, and representing a major public health issue, the multiplication of research avenues is the only possible way to one day, perhaps, shed light on the mysteries that still surround this disease affecting more than 50 million people around the world. The survey also highlights funding, which should be more ethical and equitable.

Source: Science