“You can cheat to get a paper, but you can’t cheat to cure a disease,” says scientist and physician Matthew Schrag. That’s why he turned whistleblower after finding potential fraud that may have resulted in millions of dollars and a decade of wasted research on cures for dementia.
Science, a premier, peer-review research publication, has published a six-month journalistic investigation that concluded, as Schrag suspected, that fraudulent images were used in a grounding 2006 paper on Alzheimer’s disease published in the top-tier, peer-reviewed journal Nature. Some of the photos appear to be “shockingly blatant examples of image tampering” according to experts consulted by Science. In more detail, the report reads:
The authors “appeared to have composed figures by piecing together parts of photos from different experiments,” says Elisabeth Bik, a molecular biologist and well-known forensic image consultant. “The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”
The paper, listing University of Minnesota researcher Sylvain Lesné as lead author, has been cited 2,300 times since its publication, and influencing dementia research for the last 14 years. Schrag, who first identified the potential fraud, also uncovered evidence of similar manipulation in dozens of peer-reviewed papers in the same line of research by the same scientist who published the original paper in question.
Schrag, a relatively young professor at Vanderbilt University, made his discovery after being hired in August 2021 to examine the work of pharmaceutical company Cassava Science on its experimental drug, Simufilam. Cassava Science claimed Simufilam improved mental cognition in Alzheimer’s patients.
Schrag was paid $18,000 for his investigation of Cassava’s research by the lawyer representing a couple of neuroscientists— who were also short-sellers standing to gain if Cassava Sciences’ stock fell. Scrag, not a short-seller and with no financial interest in Cassava Sciences, was motivated by the potential risk to trial participants who stood to feel side effects with no reasonable chance of benefit. His own research counters the theory on which Simufilam was based.
During his investigation, Schrag found “apparently altered or duplicated images in dozens of journal articles” used in the development of Simufilam. Science requested to see Lesné’s original images, but he refused and has not responded to requests for comment either.
Lesné’s groundbreaking paper claimed to have discovered the catalyst for accumulation of the plaque in the brain already considered a primary cause of Alzheimer’s, a type of amyloid beta, designated Aβ*56. The discovery boosted the careers of Lesné and Karen Ashe, the senior scientist who co-authored the paper, and reoriented research in Alzheimer’s and dementia, directing it towards a theory scientists were about to dismiss.
Dementia was defined in modern terms in 1838 by a French physician Dominique Esquirol. After correlating the brain autopsies of his deceased demented patients with their clinical course, he defined the characteristics of the disease as “a weakening of the sensibility, understanding, and will…Incoherence of ideas and want of intellectual and moral spontaneity.” The causes were multiple: “stroke, head trauma, syphilis, mercury poisoning, alcoholism, errors of regime, and trials, disappointments, and privation.”
In 1906 Alois Alzheimer found something Esquirol hadn’t seen. He studied the case of Augusta D., a patient with an unusual, rapidly progressive dementia, autopsying her brain after she died. Looking through his microscope, he saw the brain cells filled with thick black tangles, which he called “neurofibrillary tangles.” On the outside of the cells, he saw white “extra cellular plaque.” He proposed that these icky substances had caused the poor woman’s dementia.
For decades, medicine considered Alzheimer’s Disease a rare and specific form of dementia—prehensile dementia before it was renamed for its discoverer—and was rarely diagnosed. Then, in a research push in the 1970s, scientists found that the tangles and plaques characteristic of Alzheimer’s were more common in the brains of demented patients than previously thought, meaning Alzheimer’s was not rare. Unable to see if living patients had the signatory tangles and plaque, medicine simply changed the definition of Alzheimer’s from rapid onset prehensile dementia to any dementia that couldn’t be attributed to another cause. In theory, that meant doctors had to exclude the entire list of causes that Esquirol had developed, before attributing the dementia to plaque. Physician and historian Victoria Sweet writes in her book God’s Hotel that at first doctors made careful diagnoses. In the 1980s, though, giving patients a full Alzheimer’s examination became too time consuming and expensive, so plaque-caused dementia became the default, widely given diagnosis.
In practice for patients then, the problem is that if a demented patient is given an Alzheimer’s treatment but doesn’t have the plaque and tangles, he will suffer all the side effects of treatment targeting the plaque but without reaping any benefits—exactly what Schrag had feared for drug trial participants. Sweet watched this happen first hand with her own Alzeihmer’s patients.. Working from the original definition and diagnosis method for Alzheimer’s and dementia, she corrected many of their treatments, resulting not only in improvement but sometimes cures, particularly where the true cause was easily addressed, such as a vitamin deficiency.
Meanwhile research on Alzheimer’s was making two contradictory discoveries. In 1984, scientists identified the main component of the plaque linked with dementia as Aβ (amyloid). In 1991, researchers traced family-linked Alzheimer’s to mutations in the gene for a precursor protein that leads to amyloid. To many scientists, it seemed clear that Aβ buildup triggered cascading neuron dysfunction and damage, causing dementia. Stopping amyloid deposits became the most plausible therapeutic strategy.
Confusingly, Sweet notes, Alzheimer’s research also found that a significant number, 30% in one study, of non-dementia patients showed amyloid plaque in the brain during autopsy. Some researchers theorised that the plaque may actually be a mechanism for the brain to cure itself.
Then Ashe and Leviné’s 2006 paper came out.
It identified the precise cause of plaque build-up in the brain and confirmed the amyloid thesis as the key to developing treatments. According to Science, in the 16 years following Lesné’s landmark paper, though, only a handful of other groups have reported detecting the amyloid plaque triggering precursor Aβ*56, leading some scientists to question Lesné’s theory even before Schrag’s investigation. Significantly, no cure based on the Aβ*56 theory has emerged.
Nevertheless, not even Schrag is certain Lesné’s theory needs to be completely scrapped, and there are glimmers of hope within the body of research based on the plaque thesis, according to Science.
“The wider story potentially survives this one problem,” Schrag told Science. “But it makes you pause and rethink the foundation of the story.”
Many experts consulted by Science attributed the situation to a lack of healthy scepticism.
“Even if misconduct is rare, false ideas inserted into key nodes in our body of scientific knowledge can warp our understanding,” Schrag said.
Sweet writes in the footnotes of her memoir regarding Alois Alzheimer’s research: “In the photo of Augusta D. she looks more like a patient with a pituitary tumour than with simple dementia. One wonders.”