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After Amyloid

Updated: Jun 20

Authors of a landmark Alzheimer’s disease research paper published in the weekly science journal Nature in 2006 have agreed to retract the study in response to allegations of image manipulation. University of Minnesota (UMN) Twin Cities neuroscientist Karen Ashe, the paper’s senior author, acknowledged in a post on the journal discussion site PubPeer that the paper contains doctored images. The study has been cited nearly 2,500 times, and would be the most cited paper ever to be retracted, according to Retraction Watch data.

“Although I had no knowledge of any image manipulations in the published paper until it was brought to my attention two years ago,” Ashe wrote on PubPeer, “it is clear that several of the figures in Lesné et al. (2006) have been manipulated … for which I as the senior and corresponding author take ultimate responsibility.”

After initially arguing the paper’s problems could be addressed with a correction, Ashe said in another post last week that all of the authors had agreed to a retraction—with the exception of its first author, UMN neuro-scientist Sylvain Lesné, a protégé of Ashe’s who was the focus of a 2022 investigation by Science. A Nature spokesperson would not comment on the journal’s plans.

“It’s unfortunate that it has taken 2 years to make the decision to retract,” says Donna Wilcock, an Indiana University neuroscientist and editor of the journal Alzheimer’s & Dementia. “The evidence of manipulation was overwhelming.”

The 2006 paper suggested an amyloid beta (Aβ) protein called Aβ*56 could cause Alzheimer’s. Aβ proteins have long been linked to the disease. The authors reported that Aβ*56 was present in mice genetically engineered to develop an Alzheimer’s-like condition, and that it built up in step with their cognitive decline. The team also reported memory deficits in rats injected with Aβ*56.

For years researchers had tried to improve Alzheimer’s outcomes by stripping amyloid proteins from the brain, but the experimental drugs all failed. Aβ*56 seemed to offer a more specific and promising therapeutic target, and many embraced the finding. Funding for related work rose sharply.

But the Science investigation revealed evidence that the Nature paper and numerous others co-authored by Lesné, some listing Ashe as senior author, appeared to use manipulated data. After the story was published, leading scientists who had cited the paper to support their own experiments questioned whether Aβ*56 could be reliably detected and purified as described by Lesné and Ashe—or even existed. Some said the problems in that paper and others supported fresh doubts about the dominant hypothesis that amyloid drives Alzheimer’s. Others maintained that the hypothesis remains viable.

That debate has continued amid the approval of the anti-amyloid drug Leqembi, which modestly slows cognitive decline but carries risks of serious or even fatal brain swelling or bleeding.

Lesné, who did not reply to requests for comment, remains a UMN professor and receives National Institutes of Health funding. The university has been investigating his work since June 2022. A spokesperson says UMN recently told Nature it had reviewed two images in question, and “has closed this review with no findings of research misconduct pertaining to these figures.” The statement did not reference several other questioned figures in the same paper. UMN did not comment on whether it had reached conclusions about other Lesné papers with apparently doctored images.

“How is manipulating figures not misconduct?” asks Elisabeth Bik, a scientific integrity consultant who validated whistleblower findings about the paper for Science’s investigation. Such cases should be investigated by independent bodies, she says, not the accused scientists’ universities, which face financial and reputational conflicts of interest.

Ashe’s most recent PubPeer post maintains that “the manipulations did not change the conclusions of the experiments.” In a recent paper in iScience, she and colleagues claim to confirm the findings of the 2006 paper. “I continue to believe that Aβ*56 could play an important role in Alzheimer’s disease and targeting its removal could lead to significant clinical benefits,” she wrote on PubPeer.

In an email to Science, Ashe said Nature “declined to publish” a requested correction to the 2006 paper, making retraction “the only other option available to us.” (Nature would not comment on her account.)

“We all share the same values—preserving the integrity of the scientific record—but express them differently,” Ashe added.

Wilcock calls Ashe’s claims that her new paper replicated the Nature findings “an overstatement.” And Vanderbilt University neuroscientist Matthew Schrag, who works on scientific integrity issues independent of his employer and discovered most of the problems in Lesné’s work, disputed Ashe’s conclusions about the iScience paper in detailed comments on PubPeer. But he calls Ashe’s decision to retract “an important step in the right direction” for a field plagued with research integrity issues. “It’s taken a while, but she has taken a stand for integrity.”

Other journals that published suspect papers by Lesné have been waiting for UMN to conclude its investigation. John Foley, editor of Science Signaling, which published two of the papers, says UMN recently told him it will soon have more to say about its review.

The "what now?" if we are lucky is that all the hundreds of millions* of dollars that have been wasted on this blind alley might, over time, admittedly very slowly, be more equitably allocated to more solid science.

But do not expect Amyloid Inc. to go gently into that good night. And least not from just this one, albeit quite scandalous, blow.

More thoughtful and nuanced and even investigative reporting is sure to follow over the next days and weeks, but for now here is the best (Charles Piller writing for Science magazine online) of what is available.

And as I said in a post earlier, if you had not yet read Karl Herrup ("How Not To Study A Disease"), summer beach season might be a good time!

This story was supported by the Science Fund for Investigative Reporting.

*As suspected, it's actually billions-- more than likely hundreds of billions but certainly tens of billions. The NIH alone spent $1.6B last year on amyloid research.


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