U of A researcher tries to shore up Alzheimer’s discoveries amid image scandal

Accusations of doctored photos and manipulated Alzheimer’s research may taint the University of Minnesota, but the race for a cure raises a bigger question.

Which of the Alzheimer’s findings are valid?

The researchers, who questioned the validity of the images in the U study, said they could overturn a key 2006 discovery: a protein called abeta star 56, which independently causes memory loss in rats, is similar to the long-awaited smoking gun behind Alzheimer’s. U research leader, Dr. Karen Ashe objected to her colleague Sylvain Lesne saying it was wrong to alter the photos, but she defended the disclosure.

“While there was no editing of the selected images, the edits were immaterial, ineffective and had no bearing on the findings of the study,” he said.

Investigations by the U and the National Institutes of Health, which funded much of the research, assess whether Lesne or other authors did wrong, and scientific journals determine whether studies with questionable images require corrections or retractions.

Behind the controversy is a neurological disorder that afflicts 6 million Americans and is expected to increase as the population ages. This condition prevents thought cells, neurons, from performing cognitive or memory functions, or from sending signals to muscles and organs that tell them what to do.

While many articles raise questions, a 2006 study in the journal Nature is drawing attention because it discovered abeta star 56, or Aβ*56. Some researchers dismissed the findings as difficult to replicate, but there is little question about the study’s impact. The paper was cited thousands of times by scientists who used it as a foundation for subsequent Alzheimer’s research.

“We wouldn’t be where we are today in terms of understanding” without this study and related research, said Maria Carrillo, Alzheimer’s Association’s chief scientific officer. But as the organization prepares for its meeting in San Diego next week, it said the planned presentations are evidence that research has gone beyond the discovery.

Addressing academic deficiencies remains important, he said. “We’re self-monitoring. If we can’t trust it, it’s all over.”

U’s paper is based on the theory that the disease is linked to amyloids, proteins that accumulate abnormally in plaques and possibly block neurons. The researchers targeted the forms that dissolve over the years before the symptoms of age-related dementia appear, rather than plaques that harden.

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

At the time, the discovery that “Aβ*56 impairs memory independent of plaques or neuronal loss” was hailed by Nature as a “star suspect” in the treatment of Alzheimer’s. Today, the paper is marked with a warning to treat its results with caution until the review of the controversial images is completed.

Western blots, which use electrical charges to separate proteins and a chemical process to create visual images of them, are often studied. The size and thickness of the chemical bands produced on the film correspond to the amount of protein and whether or not it is involved in the disease.

An explosion of one spot in the Nature paper showed bands that proved the presence of Aβ*56 in rats. However, Dr. Alzheimer’s researcher Matthew Schrag of Tennessee found linear color changes around the tapes, which may have been cut and pasted. Some groups also appeared to be duplicates. Another spot showed similar peripheral dots around the bars suggesting image editing.

Schrag conducted the review outside of his job at Vanderbilt University, posted his concerns on the academic website PubPeer, and contributed to Lesne’s investigation in the journal Science in July. Experts confirmed the concern.

“This is a very sad example of human fragility and abuse,” said Dr. Dennis Selkoe, a neuroscientist at Harvard Medical School. A proponent of the Alzheimer’s amyloid connection agreed that some U images appear manipulated.

According to The Science article, Lesne manipulated images before joining Ash’s team as a research assistant in 2002 and was promoted to assistant professor at the U in 2009 with his own lab. The magazine was suspicious of Lesne, so he withdrew the paper before publishing the pictures.

Lesne did not respond to a request for comment for this story.

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

Schrag said he had not found any studies with manipulated images authored without Ash Lesne, but the concern goes beyond their 16-year-old paper. He found signs of manipulated images in a 2013 study in the journal Brain, in which U researchers confirmed the discovery of Aβ*56 in human tissue as a precursor to Alzheimer’s. The images released this year as corrections look so different that Schrag wonders if they came from the same experiment.

The bits don’t mean much to the untrained eye, but they’re the crux of the study, said Elizabeth Bick, a San Diego microbiologist turned forensic imaging consultant. He agreed that some of the images in Lesne’s papers had been manipulated.

“A scientific paper is not like a children’s book, where the pictures are there only to illuminate the whole story,” he said. “It’s different. Images, I think, are data.”

The now-controversial Nature paper has influenced years of research. Federal funding has increased for research focusing on Alzheimer’s disease in general, and amyloid in particular.

The research was necessary because amyloids are one piece of the Alzheimer’s puzzle, but the increased focus has slowed research into other key pieces, said Dr. Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center. Immune reactions and cardiovascular disease are implicated in Alzheimer’s disease, along with tau protein, which can accumulate abnormally inside neurons.

The difference is in drug development. Adukhelm received federal approval last year as an Alzheimer’s treatment that breaks down amyloid plaques, but some doctors argue that it also slows cognitive decline. Three monoclonal antibody infusions are in clinical trials; all target amyloids.

Trials of other compounds targeting amyloids have been unsuccessful. According to Ashe, it is unfair to single out the controversial U papers for such errors because they involve classes of amyloid protein that are more diverse and easier to replicate than Aβ*56.

Ash said he doubted that drugs targeting the proteins would be effective, and that amyloids were not implicated as the main cause of Alzheimer’s. His research has explored tau and other possible causes.

According to Alzheimer’s Association representative Carrillo, a few years ago limited funding forced conservative decisions to support research in areas such as amyloids. The increase has fueled bold research, and he expects Alzheimer’s treatments to come off the back of the current wave of targeting amyloid.

He said that Aβ*56 is “significantly irrelevant” to current drug research, so the idea that the U controversy could derail ongoing discoveries is “overstated and overstated.”

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