the main disease hypothesis falters

The blind attempts over the past two decades to find an effective therapy against Alzheimer’s disease they may have an explanation: they were based on a theory supported by evidence, to say the least suspect. This evidence has just been exploded after the magazine revealed Science enough to many images used in major studies of the disease have been manipulated.

This is all due to a 37-year-old neurologist from Vanderbilt University (USA) named Matthew Schrag. Last year, he exposed one of the biggest scandals in Alzheimer’s disease research when he revealed that the images used by the biopharmaceutical company Cassava to seek authorization for a drug had been manipulated.

But he didn’t stop there and, after reading in specialized forums about other possible cases of fraudulent images in various studies, he began his investigations, going back to the mid-2000s. He quickly found a thread conductor: the studies of renowned scientist Sylvain Lesné.

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Lesné’s notoriety began in 2006, when he published as first author research on molecules called “beta amyloid star 56”, abbreviated AB*56. The article appeared in the magazine Nature and is one of the most cited in its field over the past 20 years: more than 2,000 later works take it as a referencea measure of the impact of a survey.

AB*56 is a toxic oligomer, a subtype of beta-amyloid protein, that accumulates in plaques in the neurons of people with Alzheimer’s disease. This particular subtype would be more soluble in body fluids and therefore more likely to affect cells.

Alzheimer’s “smoking gun”

Although it has been known from the beginning that Alzheimer’s patients accumulate these proteins in their brains, it was unclear whether they were a cause or a consequence of the disease. Lesné’s team had isolated AB*56 from mice genetically engineered to produce large amounts of beta-amyloid and injected it into young rats that quickly showed memory problems. It was the “irrefutable proof” of the beta-amyloid hypothesis, according to which these proteins would be the cause of Alzheimer’s disease and not its consequence.

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The discovery triggered this avenue of research. According Sciencethe National Institutes of Health in the United States invested more than $1,600 million in it last year alone, half of its budget devoted to Alzheimer’s disease.

The amyloid hypothesis is the basis of new drugs that have been tested against neurodegenerative diseases over the past decade, such as infamous aducanumabwhose approval in the United States was followed by strong controversy because, despite effective destruction of plaques, there was no evidence that it improved the course of the disease.

It was Schrag’s criticism of the approval of aducanumab that prompted an investor’s attorney to hire him as a “private investigator” in the Cassava case. After the success of his investigations against the company, he did not stop there.

The neurologist found hundreds of altered images, including more than 70 in Lesné’s work, to support the impression that AB*56 was the star of the beta-amyloid hypothesis, and contacted the journals and institutions that had published or approved this work. Several items have already been removed.

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He also contacted the magazine Science, who subjected Schrag’s research to independent verification. The experts agree with the neurologist: although none – including Schrag – assert that the images were consciously manipulated to arrive at a precise conclusion, which would be synonymous with fraud, they have no doubt that most have been altered.

“Bad science and economic interests”

All of this wouldn’t be a problem if the beta-amyloid hypothesis had been beneficial, but it isn’t. Not even a year has passed since aducanumab was approved for Biogen, the company that owns the drug, to decide to stop betting on it and withdraw all commercial support.

And that’s just the tip of the iceberg. Many drugs that targeted the destruction of amyloid plaque but provided no clinical benefit have been discontinued. Several drugs survive continue to be tested on thousands of patientspresumably with better results than the previous ones, but so far none have yet been approved.

The head of the neurology department at the 12 de Octubre University Hospital in Madrid, David Perez Martinezopines that Schrag’s work “is not just a deep charge against the beta-amyloid theory, [sino que] bad science, manipulation of studies and the economic interests of a biotechnology company are mixed [Cassava] interested in developing a drug to raise high expectations in the stock market…”

In the end, he continues, “he forgets that behind all this there are huge economic interests, billions of dollars that lead to the generation of hypotheses or work that generates huge expectations. And those expectations in the world around us translate into investments and millions of dollar purchases.”

Despite this, Pérez Martínez does not believe that the disclosure will have a short-term impact on research against neurodegenerative diseases, “in the first place because there are still ongoing clinical trials based on anti-amyloid therapy and funded work in this area”, but assumes that in the medium term, “investment diversifies into other hypotheses and other projects”.

All is not lost

more skeptical Guillermo Garcia Ribasneurologist at the Ramón y Cajal Hospital, who points out that the research on AB*56 “was very relevant at the time” but that the passage of time, having not obtained results, has cooled down a bit.

He also indicates that research on oligomers had already been questioned because it had proved very difficult to replicate. If Lesné claimed to have isolated AB*56, other teams have tried to do so and found it almost impossible: when it came to purifying the samples (the preparation contains only one type of molecule), the The oligomer was unstable and eventually transformed into other subtypes.

“We will have to review the whole question of oligomers”, emphasizes García Ribas, “but there are other lines of research and the entire beta-amyloid pathway has not been challenged: protofibrils and fibrils have an important pathogenic role, for example”.

The poor results of drugs based on the beta-amyloid theory had already made more than one scientist suspicious before the revelation of Schrag and Science. The Scientific Director of the Network Center for Biomedical Research on Neurodegenerative Diseases, Adolfo López de Munain, reflected last year at EL ESPAÑOL, on the occasion of the approval of aducanumab, on the fact that this hypothesis was “manifestly insufficient”.

“This theory is, in my opinion, clearly insufficient, firstly because not only did Alzheimer – the German psychiatrist who described this disease – describe this amyloid deposit, but he also described deposits of another protein called tau And the amount of tau deposited in the brain correlates better with cognitive impairment than the amount of amyloid itself.

So far, Lesné has given no explanation, despite the fact that several of his works have been corrected. Corrections which, on the other hand, did not convince Matthew Schrag, the “neurological detective”.

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