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July 28, 2022

Is a key Alzheimer's theory based on manipulated research?

Daily Briefing

    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.

    3 big questions to ask after FDA's historic Alzheimer's drug approval

    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)

     

    Advisory Board's take

    The future of Alzheimer's research and care

    This news is yet another setback for Alzheimer's patients who have been hopefully waiting for an effective therapy. In the past few months, several pharmaceutical companies have scaled back expectations for Alzheimer's drugs in the pipeline. And this news makes many wonder whether the scientific community has been going down the wrong path as they searched for an effective treatment.

    Aside from the overall shock, we think this news raises three big questions:

    Will pharma companies change their approach to Alzheimer's R&D?

    While the amyloid approach to treatment has resulted in high-profile therapies, late-stage trails that focus on other mechanisms like inflammation or metabolism exist as well. Studies aimed at treating Alzheimer's through these long-overshadowed approaches may now become more popular and receive funding.

    Regardless of the mechanism in question, pharmaceutical manufacturers must evolve how they design clinical trials and develop evidence that supports their therapies. Moving forward, studies will almost certainly need to generate real-world evidence to prove treatment efficacy and gain broad provider and payer acceptance. But gathering this information is going to be a massive undertaking, requiring manufacturers to:

    • Enroll larger, more diverse patient populations in studies
    • Develop ways to collect data over a longer timeframe
    • Align evidence generation with clinicians' real-world evidence needs

    Will this news increase the public's mistrust of the medical community?

    We're in a moment where there is incredible mistrust of the medical community. This is leading to challenges like vaccine hesitancy and increases in misinformation. We are concerned that this news will cause mistrust between Alzheimer's patients and their physicians. This could potentially lead patients and their families to seek out alternative treatments that may ultimately prove to be harmful.

    How does this impact the way we care for Alzheimer's patients?

    Our team has been looking into how the health care industry can better care for patients with memory care disorders, including Alzheimer's. Even before this news, we were skeptical that a breakthrough treatment would emerge and be widely accessible and available. And while this is disappointing, there are other opportunities to improve care and lower costs for these patients. This includes putting a greater focus on accurate and timely diagnosis to ensure patients get connected to services, and focusing on non-pharmaceutical forms of disease management, including improving patients' lived environments, ensuring access to behavioral health specialists, and better supporting caregivers.

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