Alleged Fabrication in Alzheimer's Studies Worries Patients, Not Researchers in the Field
Article In Brief
Responding to a recent Science article alleging that images in a 2006 paper on an amyloid-beta peptide in Alzheimer's disease were fabricated, neurologists and neuroscientists dispute that the paper in question was foundational for the amyloid hypothesis and that the recent claims could undermine the field.
Within days of an article in Science alleging fabrication of images in dozens of Alzheimer's studies, worried patients participating in clinical trials began calling Thomas M. Wisniewski, MD, professor of neurology at NYU Langone Health and director of the New York State Center of Excellence for Alzheimer's Disease at the Pearl I. Barlow Center for Memory Evaluation and Treatment.
“I had fairly long conversations with a number of my patients in clinical trials for testing anti-amyloid therapies, who wondered if it was all a waste of time,” Dr. Wisniewski told Neurology Today. “I had to reassure them of the value of these types of approaches addressing aggregated amyloid-beta toxicity. The press that this is getting could tar the whole field for patients and their families.”
Other neurologists and neuroscientists have had similar experiences following publication of the July 22 Science article and coverage about it in the news media. But while decrying the possible fabrication of images in some papers, they all disputed the article's assertion that a 2006 paper in Nature served as a foundation of the amyloid hypothesis, and that questions raised about its accuracy could undermine the field today.
“If it is fraud, that is very sad,” said John A. Hardy, PhD, chair of the department of molecular neuroscience at University College London and one of the pioneers of the amyloid hypothesis in the early 1990s. “This paper has clearly been influential.... If it fraudulent, it suggests much time, effort, and money has been wasted.”
But Dr. Hardy added: “It has not been important for the amyloid hypothesis (at least in my conceptualization of it).”
The 2006 paper in Nature focused on a specific oligomer of amyloid-β protein called Abeta∗56 (spoken as “Abeta star 56”). The authors found that memory deficits in middle-aged mice bred to develop Alzheimer's were “caused by the extracellular accumulation of... Abeta∗56.”
Although the paper has been cited over 2,200 times, “the actual peptide itself (Abeta∗56) has had zero impact on activities in the therapeutic trial arena,” said David S. Knopman, MD, FAAN, professor of neurology at Mayo Clinic College of Medicine in Rochester, MN. “The three monoclonal antibody agents that are about to report their results were not directly or indirectly dependent on the Abeta∗56 claim.”
Dr. Knopman emphasized that for now, “the claim of fraud is just that—an allegation.”
In an email to Neurology Today, the senior author of the 2006 paper in Nature defended the integrity of her research into Abeta∗56.
“I have absolute confidence in the scientific accuracy of our Abeta∗56 research despite recent media reports focused on images included in a research paper from 2006,” said Karen Hsiao Ashe, MD, PhD, professor of neurology at the University of Minnesota Medical School and founding director of the N. Bud Grossman Center for Memory Research and Care. “While the editing of select images should not have occurred, the adjustments are non-material, inconsequential, and have no bearing on the research findings themselves.”
Details of the Allegations
In the mid-1990s, Dr. Ashe developed the Tg2576 transgenic mouse model of Alzheimer's disease, which develops amyloid plaques and progressive cognitive deficits. The 2006 Nature paper reported that the memory deficits seen in middle-aged Tg2576 mice were caused by Abeta∗56, and that a purified form of the oligomer taken from the brains of those impaired mice caused memory deficits when administered to young mice.
The Science article alleges possible fabrication of images in the 2006 paper, asserting that photographs of western blots were altered. The article cited independent scientists who said that similar fabrication of images appeared in other articles by the first author of the Nature paper, neuroscientist Sylvain Lesné, PhD, associate professor of neuroscience at the University of Minnesota.
“His work underpins a key element of the dominant yet controversial amyloid hypothesis of Alzheimer's,” wrote Charles Piller, a reporter for Science. If the allegations are correct, he added, “Lesné's findings were an elaborate mirage.”
According to the article, Matthew S. Schrag, MD, PhD, assistant professor of neurology and director of the Cerebral Amyloid Angiopathy Clinic at Vanderbilt University Medical Center, first raised suspicions about the accuracy of images in the paper. Other neuroscientists asked to review the images for the article agreed that many of them appeared to have been doctored. One of them, Donna M. Wilcock, PhD, professor of physiology at the University of Kentucky College of Medicine, said some of the images had “shockingly blatant” evidence of tampering.
Since July 14, the Nature paper has been amended to reflect the allegations: “The editors of Nature have been alerted to concerns regarding some of the figures in this paper. Nature is investigating these concerns, and a further editorial response will follow as soon as possible. In the meantime, readers are advised to use caution when using results reported therein.”
Alzheimer's Investigators Respond
Dr. Knopman said that Dr. Ashe is a “colleague, friend and collaborator, for whom I have the higher regard.” He said he hopes that she and Dr. Lesné are vindicated.
“It's still a possibility that the impropriety will eventually come to rest on the Vanderbilt whistleblower [Dr. Schrag] and the Science writer. But the damage has been done...once stories like this hit the national media.”
A younger Alzheimer's investigator said she had never even heard of Abeta∗56 or the paper in Nature. “I got involved in the Alzheimer's field around 2011,” said Michelle Farrell, PhD, instructor in neurology at Harvard Medical School. “By that time, it wasn't something people were talking about anymore. It's not something people really cite in relationship to the amyloid cascade hypothesis or as a target for clinical trials.”
Dr. Wisniewski said that a key reason that investigators lost interest in Abeta∗56 was that they couldn't confirm the findings of the Nature paper. “Other labs could in no way reproduce findings with Abeta∗56,” he said.
Moreover, he said, “No one ever thought there was going to be one magic species of oligomer that was responsible for the toxicity. It would be a set of different aggregated Abeta species. There's extensive data from multiple labs that aggregated Abeta species are important for neuronal toxicity and spread of pathology. That all stands.”
Grace E. Stutzmann, PhD, professor and chair of neuroscience and director of the Center for Neurodegenerative Disease and Therapeutics at Rosalind Franklin University in Chicago, agreed that the questions raised about Abeta∗56 do not undermine the widely validated findings on other amyloid subtypes. Even so, she added, “I do think this highlights how pervasive the amyloid hypothesis is and what some will do to rise to the forefront of this area of Alzheimer's research. It is seen as a hypothesis that is too big to fail, and that status can exert strong pressure to uphold it and retain the funding and resources that go with it.”
Rather than seeing the Science article as sounding a kind of death knell for the amyloid hypothesis, Dr. Farrell said she remains as hopeful as ever that trials now underway seeking to prevent the accumulation of amyloid long before clinical symptoms develop will prove successful.
“If you want to target amyloid, you have to do it at the beginning of the cascade,” she said. “It's my hope that we'll see in the next coming years results from the A4 study, using anti-amyloid therapies in people who are clinically normal but have evidence of amyloid pathology.”
Dr. Knopman disclosed that he is an investigator for an Eli Lilly trial of solanezumab and for a Biogen trial of aducanumab but receives no personal compensation.