U researcher seeks to uphold Alzheimer’s findings amid image scandal

Accusations of doctored images and manipulated Alzheimer’s disease research may tarnish the University of Minnesota, but a bigger question looms amid the race for a cure.

What about the landmark discoveries of Alzheimer’s that remain valid?

Researchers wondering if images from U studies were doctored say they could undermine a key discovery in 2006: a protein, called Abeta Star 56, that independently caused memory loss in rats and resembled the long-awaited smoking gun behind Alzheimer’s disease. The head of U research, Dr Karen Ashe, countered that a colleague, Sylvain Lesné, had been wrong to edit images, but she defended the discovery.

“While some image editing should not have taken place, the adjustments are not material, inconsequential, and have no bearing on search results,” she said.

Investigations by the U and National Institutes of Health — which funded much of the research — will assess wrongdoing by Lesné or other perpetrators, while scientific reviews will determine whether studies with suspicious images require corrections or retractions.

Behind the controversy is a vexing neurological disease that affects 6 million Americans and is expected to grow as the population ages. The condition prevents thinking cells, neurons, from performing cognitive or memory functions, or transmitting signals that tell muscles and organs what to do.

While several papers are at issue, the 2006 study in the journal Nature garners the most attention because it discovered the star beta 56, or Aβ*56. the results, but the impact of the study is not in doubt. The article has been cited thousands of times by scientists who have used it as the basis for follow-up research into Alzheimer’s disease.

“We wouldn’t be where we are today in terms of understanding,” without this study and related research, said Maria Carrillo, scientific director of the Alzheimer’s Association. However, as the organization prepares for its convention in San Diego next week, it said the planned presentations are proof that research has moved beyond that finding.

Eradicating academic irregularities remains important, however, she said. “We are self-monitoring. If we can’t rely on that, then everything collapses.”

U’s paper was based on the theory that the disease was linked to amyloids, proteins that can abnormally build up in plaques and possibly clog neurons. The researchers targeted dissolvable forms, rather than hardened plaques, that could accumulate for years before the symptoms of dementia that come with age.

U researchers have found a correlation between Aβ*56 and cognitive problems in middle-aged mice genetically bred to produce amyloid plaques. They then purified the protein and injected it into young rats, which consequently showed memory problems due to their inability to navigate a water maze.

At the time, the finding that “Aβ*56 impairs memory independent of plaques or neuronal loss” was hailed by Nature as a “star suspect” in the search for treatments for Alzheimer’s disease. Today, the article is tagged with a warning to treat its findings with caution until the review of the disputed images is complete.

Much attention is paid to Western blots, which use electrical charges to separate proteins and a chemical process to create visual representations of them. The size and thickness of the chemical bands produced on the film correspond to the amount of protein and, by extension, whether it is involved in disease.

An enlargement of a blot in the Nature article showed bands proving the presence of Aβ*56 in rats with memory loss. However, Tennessee Alzheimer’s researcher Dr. Matthew Schrag found linear discolorations around the strips suggesting they may have been cut and pasted. Some tapes have also appeared as duplicates. Another smudge showed clusters of identical peripheral dots around the bands suggesting photo editing.

Schrag, leading the review outside of his work at Vanderbilt University, posted his concerns on the academic website PubPeer and contributed to a Science magazine investigation of Lesné in July. Expert reviewers corroborated the concerns.

“This is a very sad example of human frailty and wrongdoing,” said Harvard Medical School neuroscientist Dr. Dennis Selkoe. The proponent of the amyloid link to Alzheimer’s disease agreed that some U-frames appeared manipulated.

The Science article suggested that Lesné manipulated images before joining Ashe’s team as a research assistant in 2002 and being promoted to assistant professor U with his own lab in 2009. A training supervisor Lesné’s doctoral studies at the University of Caen Normandy in France told the magazine it withdrew an article before publication because it questioned the images produced by Lesné.

Lesné did not respond to requests for comment for this story.

The U has faced this problem before, ordering the recall in 2008 of a landmark paper on adult stem cells after it was found to contain manipulated images.

Schrag said he found no studies with manipulated images in which Ashe was a non-Lesné author, but the concerns extend beyond their 16-year-old paper. He found evidence of manipulated images in a 2013 study in the journal Brain in which U researchers confirmed their findings in human tissues of Aβ*56 as a precursor to Alzheimer’s disease. The images released this year as a fix look so different that Schrag wonders if they’re from the same experiment.

The spots mean little to the untrained eye, but they are the essence of the research, said Elisabeth Bik, a San Diego microbiologist turned forensic imaging consultant. She agreed that some images in Lesné’s papers appear manipulated.

“A science paper is not like a children’s book, where the pictures are just there to shed light on the whole story,” she said. “It’s different. The images, in my opinion, are the data.”

The now disputed Nature article influenced years of research. Federal funding has increased for Alzheimer’s disease in general, but specifically for studies targeting amyloids.

The research was needed because amyloids are part of the Alzheimer’s puzzle, but increased attention has slowed studies of other key pieces, said Dr. Ronald Petersen, director of the Center for Alzheimer’s Disease Research at the Mayo Clinic. Immune reactions and cardiovascular diseases also influence Alzheimer’s disease with tau, a protein that can accumulate abnormally inside neurons.

The disparity appears in drug development. Aduhelm received federal approval last year as a treatment for Alzheimer’s disease that breaks down amyloid plaques, though some doctors question whether it also slows cognitive decline. Three infusions of monoclonal antibodies are halfway through clinical trials; all target amyloids.

Trials of other amyloid-targeting compounds have failed. Ashe said it was unfair to label the challenged U papers for such failures because they involved different and more easily replicable amyloid protein classes than Aβ*56.

Ashe said she had expressed doubts about the effectiveness of drugs targeting these proteins and was not linked to amyloid as the main cause of Alzheimer’s disease. His research explored tau and other potential causes.

Carrillo of the Alzheimer’s Association said limited funding years ago forced conservative judgments to support research in areas such as amyloid where there was early evidence. The increases have spurred bolder exploration, and she expects Alzheimer’s treatments targeting tau and inflammation to emerge just behind the current wave targeting amyloid.

Aβ*56 has been “pretty irrelevant” for current drug studies, she said, so the idea that the U controversy could undermine ongoing findings is “overblown and exaggerated.”

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