Potential fabrication in research threatens amyloid theory of Alzheimer's disease

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A version of this story appeared in Science, Vol 377, Issue 6604.Download PDF

In August 2021, Matthew Schrag, a neuroscientist and physician at Vanderbilt University, received a call that would throw him into a whirlwind of possible scientific misconduct. A colleague wanted to put him in touch with a lawyer investigating an experimental drug for Alzheimer's disease called Simufilam. The drug's developer, Cassava Sciences, claimed it improved cognition, in part by fixing a protein that can block sticky brain deposits of amyloid beta (Aβ) protein, a hallmark of Alzheimer's disease. The lawyer's clients - two prominent neuroscientists who are also short sellers profiting from the company's stock plunge - thought some research related to Simufilam may have been "fraudulent", according to a petition filed later in their name with the United States Food and Drug Administration (FDA).

Schrag, 37, a soft-spoken and nonchalantly crumpled junior professor, had previously gained notoriety by publicly criticizing the controversial FDA approval of the anti-Aβ drug Aduhelm. His own research also contradicted some of Cassava's claims. He was concerned that volunteers in ongoing Simufilam trials would face the risk of side effects with no chance of benefiting from them.

So he applied his technical and medical knowledge to interrogate published images of the drug and its underlying science, for which the attorney paid him $18,000. He identified apparently altered or duplicated images in dozens of journal articles. The attorney reported numerous findings in the FDA petition, and Schrag sent them all to the National Institutes of Health (NIH), which had invested tens of millions of dollars in the work. (Cassava denies wrongdoing [see box below].)

But Schrag's research has drawn him into a different episode of possible misconduct, leading to findings that threaten one of the most cited Alzheimer's studies of this century and many related experiments.

The first author of this influential study, published in Nature in 2006, was an ascendant neuroscientist: Sylvain Lesné of the University of Minnesota (UMN), Twin Cities. His work underpins a key element of the mainstream but controversial amyloid hypothesis of Alzheimer's disease, which holds that clumps of Aβ, known as plaques, in brain tissue are a primary cause of the devastating disease. , which afflicts tens of millions of people worldwide. In what looked like irrefutable proof of the theory and a trail of possible therapies, Lesné and his colleagues discovered an Aβ subtype and appeared to prove that it caused dementia in rats. If Schrag's doubts are correct, Lesné's findings were an elaborate mirage.

Schrag, who had not publicly disclosed his role as a whistleblower until this article, avoids the word "fraud" in his criticisms of Lesné's work and cassava-related studies and does not claim to have proven misconduct. This would require access to original, complete, unpublished images and, in some cases, raw digital data. "I focus on what we can see in the published images and describe them as red flags, not final conclusions," he says. "The data should speak for itself."

A 6-month investigation by Science has strongly supported Schrag's suspicions and raised questions about Lesné's research. A leading independent image analyst and several leading Alzheimer's disease researchers, including George Perry of the University of Texas at San Antonio and John Forsayeth of the University of California, San Francisco (UCSF), reviewed most of Schrag's findings at Science application. They agreed with his general conclusions, which cast doubt on hundreds of images, including more than 70 in Lesné's papers. Some look like "shocking and egregious" examples of image tampering, says University of Kentucky Alzheimer's disease expert Donna Wilcock.

The authors "seemed to have composed figures by assembling them...