A leading theory about the cause of Alzheimer's disease has been called into question after a Science investigation uncovered evidence of potential image manipulation in an influential 2006 study on amyloid-beta proteins.

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Investigation calls into question key Alzheimer's theory

For decades, one of the leading theories about the cause of Alzheimer's disease has been the amyloid-beta hypothesis, which suggests the disease originates from an accumulation of amyloid-beta protein that forms sticky plaques in the brain. Currently, Biogen, Roche, and Eli Lilly are testing experimental treatments that target amyloid in late-stage clinical trials.

A highly influential 2006 study published in Nature gave prominence to the theory. It examined cognitive decline in rats and identified a specific protein, Aβ*56 or amyloid beta star 56, that could be responsible for their memory loss. An accompanying editorial called the Aβ*56 "a star suspect" for causing Alzheimer's.

According to Donna Wilcock, an Alzheimer's expert and the assistant dean of biomedicine at the University of Kentucky, the discovery of Aβ*56 "was a really big finding that kind of turned the field on its head." Since then, more than 2,300 scholarly articles have cited the 2006 Nature study, and NIH support for amyloid and oligomer Alzheimer's research has grown from almost zero to $287 million a year in 2021.

However, in 2021, Matthew Schrag, a neuroscientist and physician at Vanderbilt University, raised concerns about potential image manipulation in the 2006 Nature study and other papers by Sylvain Lesné, a neuroscientist and associate professor at the University of Minnesota and the original study's lead author. In his analysis, Schrag identified images that were apparently altered or duplicated in dozens of journal articles.

Based on Schrag's findings, Science conducted its own six-month investigation into Lesné's research, asking two independent image analysts and several top Alzheimer's researchers to review the images Schrag had identified. Overall, Science found over 20 "suspect" studies by Lesné, which contained more than 70 potentially altered images.

The authors of the suspect papers "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 reviewed Lesné's work. "The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis."

Other researchers have also voiced concern that Lesné's results could not be replicated. "In my own work, [Aβ*56] was not a species ... that we had ever observed," said Thomas Wisniewski, a professor of neurology at the New York University Alzheimer's Disease Center.

According to Karl Herrup, a professor of neurobiology at the University of Pittsburgh Brain Institute who wasn't involved in the investigation, the findings are "really bad for science."

"It's never shameful to be wrong in science," Herrup said. "A lot of the best science was done by people being wrong and proving first if they were wrong and then why they were wrong. What is completely toxic to science is to be fraudulent."

"It really hurts and erodes the public trust in the scientific process," said Wilcock. "That's what is the most disturbing and upsetting to me as a scientist."

The future of the amyloid-beta hypothesis

Following an inquiry by Science, Nature on July 14 published a note saying it was investigating Lesné's 2006 paper and advised caution about the results. Other journals, including Science Signaling, have also said they are investigating certain Lesné studies they've published.

Kat Dodge, a spokesperson for the University of Minnesota Medical School, said the school is aware of the potential issues in Lesné's studies and "will follow its processes to review the questions any claims have raised."

Separately, Karen Ashe, a neuroscientist and professor at the University of Minnesota who co-authored the 2006 study with Lesné, said she wanted to retract the study, as confidence in it has been undermined. Although Ashe and others worked with Lesné on the study, Lesné prepared the images for publication, Science reports.

"Having worked for decades to understand the cause of Alzheimer disease, so that better treatments can be found for patients, it is devastating to discover that a co-worker may have misled me and the scientific community through the doctoring of images," Ashe said. However, she argued that a retraction "does not call the amyloid-beta hypothesis into question."

Other researchers similarly said that while studies of Aβ*56 should come under new scrutiny, the overall theory should be not discredited.

According to Herrup, Lesné's work was not the only piece of influential piece of Alzheimer's research over the past 20 years. "There were so many other forces driving that conceptualization of the disease," he said.

"Rare examples of malfeasance and fraud occur in all fields of human endeavor, and I do not feel Sylvain Lesné's acts are a reflection of AD research over the last four decades," said Dennis Selkoe, co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women's Hospital.

However, other scientists say the Science investigation bolsters their belief that too much Alzheimer's research has focused on amyloid instead of other potential causes.

"For many of us, this is not surprising," said Brian Silver, interim chair of the department of neurology at UMass Memorial Health. "The amyloid hypothesis has been challenged for at least a decade. While having amyloid accumulation may be necessary for the disease to occur, it is alone not sufficient. Autopsy studies show patients with significant accumulation of amyloid and no evidence of dementia during life. The current thinking is that another protein (tau) may actually be the driver of the disease progression." (Bendix/Chow, NBC News, 7/25; Saltzman/Cross, Boston Globe, 7/25; Piller, Science, 7/21)