University of Minnesota scientist responds to fraud allegations in Alzheimer's research

A senior University of Minnesota scientist said it is "devastating" that a colleague might have doctored images to prop up research, but she defended the authenticity of her groundbreaking work on the origins of Alzheimer's disease.

Dr. Karen Ashe declined to comment about a U investigation into the veracity of studies led by Sylvain Lesné, a neuroscientist she hired and a rising star in the field of Alzheimer's research. However, she criticized an article in Science magazine that raised concerns this week about Lesné, because she said it confused and exaggerated the effect the U's work had on downstream drug development to treat Alzheimer's-related dementia.

"Having worked for decades to understand the cause of Alzheimer disease, so that better treatments can be found for patients, it is devastating to discover that a co-worker may have misled me and the scientific community through the doctoring of images," Ashe said in an e-mail Friday morning. "It is, however, additionally distressing to find that a major scientific journal has flagrantly misrepresented the implications of my work."

Questions have surfaced about as many as 10 papers written by Lesné, and often coauthored by Ashe and other U scientists, and whether they used manipulated or duplicated images to inflate the role of a protein in the onset of Alzheimer's.

The Science article detailed efforts by Dr. Matthew Schrag, an Alzheimer's researcher in Tennessee, who colorized and magnified images from Lesné's studies in ways that revealed questions about whether they were doctored or copied. Expert consultants agreed in the article that some of the images in the U studies appeared manipulated in ways that elevated the importance of a protein called Aβ*56.

Many of the images were of Western blot tests showing that Aβ*56, also called amyloid beta star 56, was more prevalent in mice that were older and showed signs of memory loss.

The U studies have been so influential on the course of Alzheimer's research over the past two decades that any evidence of manipulation or false study results could fundamentally shift thinking on the causes of the disease and dementia. The investigation also implicates two successful researchers on a key measure by which they are judged: their ability to pull in federal grants.

Lesné was a named recipient of $774,000 in National Institutes of Health grants specifically involving Aβ*56 from 2008 through 2012. He subsequently received more than $7 million in additional NIH grants related to the origins of Alzheimer's.

Lesné, who did not reply to an e-mail asking for comment, came to the U in 2002 as a postdoctoral research associate after earning his doctorate at the University of Caen Normandy. He took charge of his own U lab by 2009 and became associate director of graduate studies in the neuroscience program in 2020. He was the first- or last-named author on all of the disputed studies, meaning he either instigated the research or was the senior scientist overseeing the work.

Ashe said there are two classes of Aβ proteins, which she refers to as Abeta, and that her efforts have focused on one while drugmakers have unsuccessfully targeted the other with potential Alzheimer's treatments. As a result, she said it was unfair of the Science article — even as it raised concerns about research improprieties — to pin an entire industry's lack of progress on the scrutinized U research.

"It is this latter form that drug developers have repeatedly but unsuccessfully targeted," she said. "There have been no clinical trials targeting the type 1 form of Abeta, the form which my research has suggested is more relevant to dementia. [The article] has erroneously conflated the two forms of Abeta."

The scientific journal Nature is reviewing a 2006 study led by Lesné regarding the existence and role of Aβ*56 and urging people to use it cautiously for now. Concerns emerged in part because researchers at other institutions struggled to replicate the results.

Two other 2012 and 2013 papers were corrected earlier this year, with U researchers acknowledging errant images but stating that they didn't affect the overall conclusions. However, Schrag said he has concerns the corrected images also were manipulated.

"I think those corrected images are quite problematic," he said.

Beneath the research controversy is a fundamental search and debate over the causes of Alzheimer's and related dementia. One theory is that certain Abeta proteins result in the development of amyloid plaques, which clog up space between nerve cells in the brain and inhibit memory and cognition. Another is that tau proteins clump inside the brain's thinking cells and disrupt them.

Ashe's research has explored both possibilities. Since 1986, she has been a named recipient of more than $28 million in NIH grants, making her one of the most productive researchers in U history.

Complicated legacy

Despite a remarkable history of life-saving inventions and surgical accomplishments, the U also has a legacy of research stars being implicated in scandals.

The late Dr. S. Charles Schulz stepped down as U psychiatry chair in 2015 amid claims by a grieving family that their son, who died by suicide, was coercively recruited into a schizophrenia drug trial.

Duplicated images and errors forced the correction of a 2002 Nature study, led by Dr. Catherine Verfaillie, claiming that certain adult stem cells possessed flexible abilities to grow and develop other cell types.

The late Dr. John Najarian was a pioneer in organ transplantation who elevated the U's global profile, but he faced federal sanctions in the 1990s related to illicit sales of an experimental anti-rejection medication that improved transplant outcomes.

A U investigation of Lesné's work will follow its standard policy of research misconduct allegations, according to a statement from the medical school.