The Alzheimer’s field was rocked this week by allegations against Sylvain Lesné at the University of Minnesota, Minneapolis. Lesné stands accused of manipulating data images in multiple papers, including his 2006 Nature paper identifying Aβ*56 as a toxic oligomer associated with cognitive decline. The potentially altered images were found by neuroscientist Matthew Schrag at Vanderbilt University. Earlier this year, Schrag alerted the National Institutes of Health and UMN, as well as the journals that published the papers. Multiple investigations are ongoing.

A July 21 Science article by investigative journalist Charles Piller broke the news to the field at large. Science magazine conducted its own six-month investigation, in which independent analysts agreed the images showed signs of tampering.

Alzheimer’s researchers expressed dismay. Most thought that even if the allegations are confirmed, the impact on oligomer research would be much smaller than the general effect of bringing disrepute to the field. “The refutation of Aβ*56 would have no impact on the huge weight of evidence that supports a role for soluble aggregates (aka oligomers) in AD,” Dominic Walsh at Brigham and Women’s Hospital, Boston, wrote to Alzforum. Mathias Jucker at the University of Tübingen, Germany, concurred. “The Aβ*56 work was just one paper among many others claiming that Aβ oligomers are the key toxic species in AD pathogenesis. I do not think the field would have developed differently without the Lesné work,” he wrote.

“I am speechless about these allegations. This damages the reputation of the oligomer research field, where much good work is being done,” Christian Haass of DZNE Munich wrote to Alzforum (full comments below).

Copies? In Lesné’s 2006 Nature paper on Aβ*56, these western blot bands ostensibly represent two different control proteins, but instead are exact duplicates of each other. [Courtesy of Science/AAAS.]

Lesné identified Aβ*56 while in Karen Ashe’s lab at UMN. The finding made a splash at the time, generating excitement as a potential link between a specific Aβ oligomer and cognitive decline (Mar 2006 news). However, few if any subsequent papers have been published on it outside of Ashe and Lesné’s labs. Likewise, other scientists working on aggregated Aβ wrote that they were unaware of independent corroboration (comments below).

Many Alzheimer’s researchers told Alzforum, some off the record, that they tried but were unable to replicate the findings. Most did not publish those efforts. One who did was Dennis Selkoe at Brigham and Women’s. At the time, Selkoe reported being unable to find the species in both human cortical extracts and cerebrospinal fluid (Shankar et al., 2008; Klyubin et al., 2008). 

Schrag became aware of potential problems with Lesné’s work while being contracted to investigate an entirely separate issue, namely allegations against biotech Cassava Sciences over its drug simufilam. As part of that investigation, Schrag found issues in 34 published papers, including one that laid the groundwork for the hypothesis that AD is “Type 3 diabetes” (Talbot et al., 2012).

In the course of that unrelated work, Schrag perused PubPeer, an online site where researchers flag suspected problems in published work. Schrag spotted complaints about figures in Lesné’s work. Digging deeper, he flagged figures in 20 Lesné papers; 10 of which involved Aβ*56. The problems included duplicated bands on western blots (see image above), as well as images that seemed to be composites from different experiments, or figures reprinted in later papers as though new. Lesné did not respond to a request for comment from Alzforum.

Schrag found no suspicious figures in papers from the Ashe lab where Lesné was not a co-author. Ashe is not under investigation.

Schrag submitted his concerns to NIH in January 2022 and alerted the journals in question. In response, at least two journals, Nature and Science Signaling, have published “expressions of concern” about the papers, and are investigating. UMN also says it is reviewing the matter. NIH whistleblower complaints are typically referred to the Office of Research Integrity; investigations there can take years.

Schrag also contacted Science. The journal showed the data to two independent image analysts, Elisabeth Bik and Jana Christopher, as well as to Alzheimer’s researchers including Selkoe; George Perry at the University of Texas, San Antonio; Donna Wilcock at the University of Kentucky, Lexington; and John Forsayeth at the University of California, San Francisco. All agreed there were genuine issues with the figures.

Piller also uncovered previous suspicions about Lesné’s work. His postdoc supervisor Denis Vivien at the University of Caen Normandy, France, told Science that he withdrew a manuscript he had been co-authoring with Lesné over doubts about some immunostainings, and that others in his lab were unable to replicate them.

Ashe declined to comment on the allegations against Lesné, but stands by the science behind Aβ*56. “Staff scientists in our labs regularly and reproducibly detect Aβ*56 in a subset of Tg2576 and J20 mice,” she wrote to Alzforum (full comment below).

Ashe’s group initially reported finding the species in human CSF; however, a subsequent paper suggested that could have been an artifact, with the bands perhaps being confounded by N-terminal amyloid precursor protein fragments (Mar 2013 news; Grant et al., 2019). Another recent paper from the lab implied that the Aβ*56 bands in earlier publications could have been artifacts of using the biotin-avidin system and/or Protein A shed from Sepharose beads (Grant et al., 2019). 

Whatever the effect of the allegations on Aβ*56 and oligomer research, AD researchers agreed they give the field a black eye. “This is not a real scientific problem, but it is most unfortunate for general science credibility,” Selkoe wrote to Alzforum.

Others noted that the scientific process tends to ferret out results that cannot be reproduced. “I am very disappointed to read this article of possible ‘fabrication’ in this field. But science is self-correcting, and this is a good example,” Colin Masters at the University of Melbourne, Australia, wrote to Alzforum.—Madolyn Bowman Rogers

News Citations

  1. Aβ Star is Born? Memory Loss in APP Mice Blamed on Oligomer
  2. Aβ*56 Found in Human CSF, Correlates With Tau?

Therapeutics Citations

  1. Simufilam

Paper Citations

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    Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory.
    Nat Med. 2008 Aug;14(8):837-42.
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    Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization.
    J Neurosci. 2008 Apr 16;28(16):4231-7.
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    Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.
    J Clin Invest. 2012 Apr;122(4):1316-38.
  4. .
    Human cerebrospinal fluid 6E10-immunoreactive protein species contain amyloid precursor protein fragments.
    PLoS One. 2019;14(2):e0212815. Epub 2019 Feb 28
  5. .
    A Cautionary Tale: Endogenous Biotinylated Proteins and Exogenously-Introduced Protein A Cause Antibody-Independent Artefacts in Western Blot Studies of Brain-Derived Proteins.
    Biol Proced Online. 2019;21:6. Epub 2019 Apr 18