Potential Research Fabrication Bombshell Threatens Amyloid Theory of Alzheimer’s Disease

Alzheimer’s disease is a form of progressive dementia that we’ve labored to figure out for decades. Scientists made some headway with the amyloid hypothesis of Alzheimer’s disease, but progress is slow, and the hypothesis is incomplete. Now, a startling report has surfaced, accusing a prestigious Alzheimer’s researcher of systemic, deliberate research fraud. The results of this investigation could imperil the amyloid hypothesis as a whole.

The amyloid hypothesis of Alzheimer’s disease names a sticky protein called amyloid-beta as the disease’s primary cause. Scientists have identified “plaques and tangles” of amyloid-beta (Aβ) and tau (T) proteins in the brains of people who died of Alzheimer’s disease. But the amyloid hypothesis of the disease doesn’t fully explain its symptoms. Nor does it explain the scattershot absence of the protein in some Alzheimer’s victims’ brains.

But in 2006, Sylvain Lesné, of the University of Minnesota (UMN), shook up the Alzheimer’s research community with an extraordinary claim. Lesné and his team reported that they had discovered a “56-kDa soluble amyloid-β assembly,” a type of amyloid molecule which caused memory disruptions when they injected it into the brains of rats. (The “56-kDa” means 56 kiloDaltons, and it refers to the protein’s molecular weight.)

In the report, the authors propose that “Aβ*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer’s disease.”

‘Aβ Star is Born’

It looked like a smoking gun. The 2006 paper made it to Nature, one of the big-name scientific publishing houses. Alzforum, a “widely read online hub” for researchers, titled its writeup “Aβ Star is Born?” So, researchers leapt to explore the possibility of a treatment for Alzheimer’s that suppressed our Aβ precursor genes, or scrubbed Aβ itself from the brain.

Since then, much work has focused on amyloid plaques. More than two thousand papers cite Lesne’s 2006 paper. But it’s slow going. Since the amyloid explanation took precedence, it’s become difficult to get funding for research into other treatments or causes for the disease. Scientists complain that they’ve been sidelined by the “amyloid mafia.” However, none of the amyloid research resulted in a drug or treatment that slows, stops, or cures Alzheimer’s. That is, until Biogen debuted aducanumab.

Late in 2021, the FDA approved aducanumab, or Aduhelm: a monoclonal antibody targeting Aβ. But the drug hasn’t lived up to its promises. Aduhelm is the subject of tremendous controversy, because the FDA approved it despite massive scientific outcry.

Plaques Entangled

Aduhelm actually had to try for FDA approval twice. The first time Biogen sought approval for aducanumab, it fell short because its research receipts didn’t add up. The drug had flunked out of two prior Phase III clinical trials. Two internal FDA reviews of Aduhelm dismantled its claims. But, for reasons, Biogen decided to put Aduhelm forth for approval again.

The second time around, Biogen’s own data showed Aduhelm had failed one of its two new trials. They also showed that some 40 percent of people who got the FDA-approved higher dosage developed brain swelling. When the FDA gave Aduhelm fast-track approval, three members of the FDA’s advisory committee resigned in protest.

All this was already piling up when an aducanumab whistleblower named Matthew Schrag quietly approached Science with allegations that Lesné had engaged in widespread, deliberate research fraud. Science‘s six-month investigation uncovered a history of scientific misconduct shadowing Lesné’s twenty-year career. The results could spell disaster for the entire amyloid theory — and for Aduhelm.

‘Unmistakable differences’

Schrag himself carefully avoids the use of the word “fraud.” Without the raw data, he says, he can’t prove misconduct. “I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he says. “The data should speak for itself.”

And speak it does.

Science conducted its own investigation of Lesné and his work. When its findings corroborated Schrag’s suspicion of tampering, Science reached out to top Alzheimer’s researchers and independent image analysts. They, too, concurred with Schrag’s report.

The authors “appeared to have composed figures by piecing together parts of photos from different experiments,” said Elisabeth Bik, a molecular biologist and forensic image consultant who worked with Schrag on the Science investigation. “The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”

Science‘s investigation also worked with Harvard neuroscientist and amyloid expert Dennis Selkoe, who called the situation “worrying” and “highly egregious.”

“We need to declare these examples,” said Selkoe, “and warn the world.”

‘There is no other explanation’

Jana Christopher, another image analysis expert, identified other suspicious blots and images Schrag had missed. Selkoe, who had himself coauthored a paper with Lesné, dug through Lesné’s work for signs of manipulation. And the findings were grim. “There are certainly at least 12 or 15 images,” said Selkoe, “where I would agree that there is no other explanation.”

In total, the investigation found more than 20 suspect Lesné papers. Ten of them concerned Aβ*56. But one of the suspect papers was Lesné’s original 2006 Aβ*56 report.

Lesné’s work is important to the amyloid hypothesis as a whole. So it’s especially troubling that his amyloid research should fall apart under scrutiny. Biogen developed Aduhelm using data from Lesné’s original Aβ*56 paper.

When Science broke the news of their investigation, Nature parked a warning at the top of Lesné’s 2006 article.

Deflect, Deny, Distract

Science approached Karen Ashe, one of Lesne’s frequent coauthors, for comment. Ashe declined to be interviewed or to answer Science’s written questions. But shortly afterward, she took to PubPeer to defend the work.

Ashe’s post includes portions of the original images from her 2006 work with Lesné. The images don’t show the cut marks from Schrag’s report — which would suggest that the marks were just publishing artifacts. But in those images, Schrag and Selkoe found still more “unequivocal evidence” of tampering. Despite the lack of obvious cut marks, multiple bands were copied and pasted.

So far, Lesné and his collaborators have published two corrections. One, which concerned a 2012 paper in The Journal of Neuroscience, replaced several images that the Science investigation had flagged as “problematic.” Lesné wrote that the original versions had been “processed inappropriately.” But Schrag says even the corrected images still show signs of tampering in the DNA bands. In one paper, someone appears to have completely replaced a blot.

Ashe’s solo work passes authenticity checks, which suggests she’s innocent of misconduct. But this still appears to be a major ethical lapse. Even if Ashe herself didn’t do the dirty work, she was the senior investigator. “I don’t see how [Ashe] would not hyperscrutinize anything that subsequently related to Aβ*56,” said Selkoe.

Lesné did not respond to requests for comment.

Correctile Dysfunction

Lesné and Ashe were the first and senior authors, respectively, of a 2013 Brain paper which also received extensive correction in May of this year. Schrag had flagged multiple images in the study, which showed “negligible” levels of Aβ*56 in children and young adults, increasing steadily after about 40 years of age. The paper concluded that Aβ*56 “may play a pathogenic role very early in the pathogenesis of Alzheimer’s disease.”

The study authors said the correction had no bearing on the study’s findings. But Schrag isn’t convinced. Among other problems, one corrected blot still shows signs of tampering.

“I still have faith in Aβ*56,” Ashe told Science, pointing out her ongoing work studying Aβ oligomers. “We have promising initial results. I remain excited about this work, and believe it has the potential to explain why Aβ therapies may yet work despite recent failures targeting amyloid plaques.”

And Joseph Smith blamed the printer for the fact that he couldn’t reproduce the first chapters of the Book of Mormon.

Citation Needed

Science is facing a global reproducibility crisis. One 2021 analysis estimated that half of American psychology research reports can’t be reproduced. America has its trailblazing fraudsters. Theranos and its very public implosion come to mind. But the situation is at least this bad overseas. In a damning internal report, the Chinese FDA estimated that fully 80% of the new drug registration applications it receives are “fraudulent or substandard.”

If the amyloid hypothesis falls, Biogen’s stock price will fall with it.

Meanwhile, Schrag is betting his career on these bombshell allegations. Calling out influential researchers and journals could come back to bite him. But he says it’s worth it.

“You can cheat to get a paper. You can cheat to get a degree. You can cheat to get a grant,” says Schrag. “[But] you can’t cheat to cure a disease. Biology doesn’t care.”