A highly-cited paper on Alzheimer's Disease, published in the journal Nature in 2006, may have involved the alteration of images to back up the results, an investigation published in Science has alleged.

Sometime last year, two neuroscientists contacted Mathew Schrag – a neuroscientist and physician at Vanderbilt University – to help them in an investigation into the drug Simufilam, and its developer Cassava Sciences. The neuroscientists, who are short sellers who make a profit if Cassava Sciences' stock falls, believed that they may have spotted potentially fraudulent activities in research related to the drug, and filed a petition with the Federal Drug Administration (FDA) to halt trials on the experimental drug "pending audits of 1 the publications relied on by Cassava in support of its scientific claims concerning Simufilam".

Schrag – whose own research was at odds with claims made by Cassava – took on the investigation, going through published images from research relating to the drug or the science behind it. 

According to Schrag and a subsequent investigation by Science, a key piece of research – which claimed to show that the accumulation of Aβ clumps (plaques) in the brain "may contribute to cognitive deficits associated with Alzheimer's disease" – may involve image tampering. Specifically, these claims relate to the oligomer of Aβ termed Aβ*56.

Science asked several experts to review images that Schrag had found to contain "red flags". According to one Alzheimer's expert at the University of Kentucky – Dr Donna Wilcock – image tampering in the research published by Sylvain Lesné of the University of Minnesota seems to be "shockingly blatant".

"It’s blatant, persistent, and unforgivable," Wilcock expanded on Twitter. "Lesné appears to have repeatedly manipulated western blot images to pitch a story that has been irreproducible by scientists in our field."

According to molecular biologist and well-known forensic image consultant Elisabeth Bik, the authors of the paper “appeared to have composed figures by piecing together parts of photos from different experiments.” She told Science "the obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”

Concerns about images in papers authored by Lesné appear to have been raised independently on online "journal club" PubPeer.

While the allegations are big, and the implications for Alzheimer's research – and the time and money potentially spent going down a false path – are huge too, claims about the size of the scandal may have been overblown since the piece in Science was published.

"The impact on the field is somewhat overstated," Wilcock, who had reviewed the images as part of the investigation, wrote on Twitter. "Those of us working in the field have understood for some time this work is not reproducible – science just lacks the ability to publish such findings so word-of-mouth is how this is known."

While serious, people within the field – including Alzheimer's Research UK – stress that if the allegations are correct, the impact is not as big as it may appear from the outside.

"The main paper at issue here did NOT establish the amyloid plaque model. It discussed a specific oligomer of AB termed AB*56.  There are plenty of other papers in the field showing importance and effects of oligomers and insoluble amyloid (plaque) species on numerous factors," Alzheimer's postdoc Samuel Marsh wrote on Twitter.

"I sincerely doubt that the absence of this particular paper and AB*56 from historical scientific record would have significantly changed the last 20 years of [Alzheimer's] drug development.  That is because there is strong genetic and other evidence for the role of amyloid in disease."

Meanwhile, Prof Sir John Hardy from University College London, who developed the amyloid hypothesis in the 1990s, told Alzheimer's Research UK that he was skeptical of the impact this paper has had.

“I have never thought this paper was important, and I don’t think I have ever referred to it in my own work,” Hardy told Alzheimer's Research UK, adding “it is a shame if these papers involve deceit, and journals and institutions need to crack down on fraud when it is discovered."

Lesné is currently under investigation by the University of Minnesota, where he is an associate professor.

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