Alleged Fabrication in Alzheimer’s Studies Worries Patients,…: Neuroscience Today

By Dan Hurley

September 15, 2022

Article in brief

Reply to Hadith Sciences Article Alleging Images In a 2006 research paper on the amyloid beta peptide in Alzheimer’s disease, neuroscientists and neuroscientists argue that the paper in question was the basis for the amyloid hypothesis and that recent claims could undermine the field.

Within days of publishing an article in Sciences Claiming to fabricate images in dozens of Alzheimer’s studies, anxious patients participating in clinical trials began contacting Thomas M. Wisniewski, MD, professor of neuroscience at NYU Langone Health and director of the New York State Alzheimer’s Center of Excellence at Pearl Eye. Barlow Center for Memory Assessment and Treatment.

“I’ve had fairly long conversations with a number of my patients in clinical trials testing anti-amyloid therapies, who wondered if it was all a waste of time,” said Dr. Wisniewski. Neuroscience Today. “I had to reassure them of the value of these kinds of approaches that treat accumulated amyloid-beta toxicity. The press that is obtained can contaminate the entire field for patients and their families.”

Other neurologists and neuroscientists had similar experiences after the July 22 publication Sciences Article and coverage about it in the media. But while they decried the possibility of the images being fabricated in some papers, they all disputed the article’s assertion that the 2006 paper in temper nature It served as the basis for the amyloid hypothesis, and that questions raised about its accuracy could undermine the field today.

“If it’s fraud, it’s 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. “Obviously this paper was impressive…if it was fraudulent, it indicates a lot of time, effort and money wasted.”

But Dr. Hardy added: “It wasn’t significant for the amyloid hypothesis (at least in my perception of it).”

2006 paper in temper nature Focus on a specific oligomer of the amyloid beta protein called Abeta ∗ 56 (pronounced “Abeta star 56”). The authors found that the memory deficits in middle-aged mice bred to develop Alzheimer’s disease “was caused by the extracellular accumulation of … Abeta ∗56”.

Although the research paper was cited more than 2,200 times, “the actual peptide itself (Abeta ∗ 56) had no effect on activities in the therapeutic trial arena,” said David S. Knopman, MD, FAAN, professor of neurology at Mayo Clinic College of Medicine in Rochester, Minnesota. “The three monoclonal antibody agents whose results are about to be reported were not directly or indirectly dependent on the Abeta ∗56 claim.”

Dr. Knopman emphasized that for now, “the allegation of fraud is just an allegation.”

In a letter to Neuroscience Todaylead author of a 2006 paper in temper nature She defended the integrity of her research on Abeta ∗56.

“I have absolute confidence in the scientific accuracy of our Abeta ∗56 research despite recent media reports that focused on images included in a research paper from 2006,” said Karen Hsiao Ash, MD, PhD, professor of neurology at the University of Minnesota School of Medicine. and founding director of the N. Bud Grossman Center for Memory Research and Care. “While editing the selected images should not have occurred, the edits are immaterial, insignificant and have no effect on the search results themselves.”

Allegations details

In the mid-1990s, Dr. Ash developed a transgenic Tg2576 mouse model of Alzheimer’s disease, which develops amyloid plaques and progressive cognitive deficits. 2006 temper nature The paper reported that the memory deficits seen in middle-aged Tg2576 mice were caused by Abeta ∗56, and that the purified form of oligomers taken from the brains of those inactivated mice induced memory deficits when administered to young mice.

The Sciences The article alleges the possible fabrication of the images in a 2006 paper, asserting that the images of the western blots have been altered. The article cited independent scholars who said similar fabrication of images appeared in other articles by the first author of temper nature paper, neuroscientist Sylvain Lesne, Ph.D., associate professor of neuroscience at the University of Minnesota.

“I’ve had fairly long conversations with a number of my patients in clinical trials testing anti-amyloid therapies, who wondered if it was all a waste of time. I had to reassure them of the value of these kinds of approaches that treat amyloid-beta toxicity. The press that It can contaminate the entire field for patients and their families.” – Dr. Thomas M. Wisniewski

Figure 2

“I have absolute confidence in the scientific accuracy of our Abeta 56 research despite recent media reports that focused on the images included in a research paper from 2006. While the editing of the specific images should not have occurred, the edits are immaterial, illogical, and have no effect. on the same search results. – Dr. Karen Hsiao Ash

Charles Beller, a reporter for . wrote Sciences. He added that if the allegations were true, “Lesny’s findings were a detailed mirage.”

According to the article, Matthew S. Other neuroscientists, who asked to review the images for the article, agreed that many of them appeared to have been manipulated. One of them, Donna M. Wilcock, professor of physiology at the University of Kentucky School of Medicine, said some of the photos had “shockingly stark” evidence of manipulation.

Since July 14, temper nature The paper has been modified to reflect the claims: “The editors of Nature have been alerted to concerns about some of the numbers in this paper. temper nature Investigate these concerns, and another editorial response will follow as soon as possible. In the meantime, readers are advised to exercise caution when using the results presented in it.”

Alzheimer’s disease investigators respond

Dr. Knopman said Dr. Ash is “a colleague, friend, and collaborator, and I appreciate him very much.” He said he hoped she and Dr. Lesny would be acquitted.

“It is still possible that the infractions will ultimately fall to the Vanderbilt whistleblowers [Dr. Schrag] and the Sciences clerk. But the damage was done…once such stories hit the national media.”

A younger Alzheimer’s investigator said she had never heard of Abeta ∗56 or the paper in it temper nature. “I got involved in the Alzheimer’s field around 2011,” said Michelle Farrell, MD, professor of neurology at Harvard Medical School. “By then, this is not something people are talking about anymore. It is not something people are really citing in relation to the amyloid cascade hypothesis or as a target of clinical trials.”

Dr. Wisniewski said the main reason the investigators lost interest in Abeta ∗56 was because they were unable to confirm the research findings. temper nature paper. “In no way can other laboratories reproduce the results with Abeta ∗56,” he said.

Furthermore, he said, “No one ever thought that there would be one magical type of oligomer responsible for the toxicity. It would be a combination of different types of Abeta. There is extensive data from multiple laboratories that the combined Abeta species are important for neurotoxicity and the spread of science Diseases. That’s it.”

Grace E. Stutzman, PhD, professor and chair of neuroscience and director of the Center for Neurodegenerative Diseases and Treatment at Rosalind Franklin University in Chicago, agreed that the questions raised about Abeta ∗56 do not undermine the widely validated findings on other subtypes of amyloid; However, she added, “I think this highlights how prevalent the amyloid hypothesis is and what some will do to advance in this area of ​​Alzheimer’s research. It is seen as a hypothesis too big to fail, and this case can exert strong pressure to support it and retain the funding and resources that it accompany it.”

instead of seeing Sciences While it sounds like a kind of death knell for the amyloid hypothesis, Dr. Farrell said she remains as optimistic as ever that the trials now underway that seek to prevent amyloid buildup long before clinical symptoms appear will prove successful.

“If you want to target amyloid, you have to do it at the beginning of the chain,” she said. “I hope in the coming years we will see the results of the A4 study, using anti-amyloid therapies in people who are clinically normal but have evidence of amyloid pathology.”

Disclosures

Dr. Knopman revealed that he was an investigator in Eli Lilly’s trial of solanezumab and in Biogen’s trial of aducanumab but that he received no personal compensation.