The Alzheimer’s field was rocked this week by allegations against Sylvain Lesne at the University of Minnesota, Minneapolis. Lesne has been identified in several papers, including a 2006 Nature paper, as a toxic oligomer associated with cognitive decline in Aβ*56. The potentially altered images were discovered 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 articles. Many investigations are ongoing.

Investigative journalist Charles Piller broke the news in a July 21 issue of Science. The journal Science conducted its own six-month investigation, in which independent analysts agreed that the images showed signs of manipulation.

Alzheimer’s researchers have expressed concern. Most believed that even if the claims were confirmed, the impact on oligomeric research would be far less than the overall impact of discrediting the field. “The Aβ*56 refutation does not affect the overwhelming weight of evidence supporting the role of soluble aggregates (aka oligomers) in AD,” Dominic Walsh of Brigham and Women’s Hospital in Boston wrote to Alzforum. Mathias Uecker from the University of Tübingen, Germany competed. “The Aβ * 56 case was just one of many other papers arguing that Aβ oligomers are the main toxic species in AD pathogenesis. I don’t think the field would have progressed any differently without Lesne’s work,” he wrote.

“I am not silent about these accusations. This damages the reputation of the field of oligomeric research, where a lot of good work is being done,” wrote Christian Haas of DZNE Munich to Alzforum (full comments below).

Copies? Lesne’s 2006 book “Nature” Aβ*56, these western blot bands apparently represent two different control proteins, but are instead exact copies of each other. [Courtesy of Science/AAAS.]

Lesné discovered Aβ * 56 while in Karen Ash’s lab at UMN. This finding caused excitement at the time as a potential link between a specific Aβ oligomer and cognitive decline ( March 2006 news release ). However, there are few subsequent papers outside of Ash and Lesne’s labs. Similarly, other scientists working on aggregated Aβ have written that they know of no independent confirmation (comment below).

Many Alzheimer’s researchers told Alzforum, some off the record, that they had tried but failed to replicate the findings. Most did not publish those actions. One of them was Dennis Selkoe of Brigham and Women. At that time, Selkoe reported that he was unable to detect the species in either human cortical extracts or cerebrospinal fluid (Shankar et al., 2008; Klyubin et al., 2008).

Schrag was aware of the potential problems in Lesne’s case when he contracted an entirely separate matter, namely the biotech company Cassava Sciences, to investigate claims against its simufilam drug. As part of that investigation, Schrag found issues in 34 published articles, including one that provided the basis for the AD “type 3 diabetes” hypothesis (Talbot et al., 2012).

During that unrelated case, Schrag reviewed the online site PubPeer, where researchers flag suspected problems with published work. Schrag noted complaints about figures in Lesne’s work. Digging deeper, he notes the numbers on 20 Lesné papers; Of these, 10 were involved in Aβ*56. Problems include duplicate bands in western blots (see image above), as well as images that appear to be composites of different experiments or figures that appear to be reprinted in later papers. Lesné did not respond to Alzforum’s request for comment.

Schrag found no suspicious figures in the Ashe lab papers, where Lesne was not a co-author. Investigations are not conducted on his case.

Schrag submitted his concerns to the NIH in January 2022 and alerted the journals in question. In response, at least two journals, Nature and Science Signaling, have published “statements of concern” about the papers and are investigating. UMN also said that it is looking into this matter. NIH reporting complaints are usually submitted to the Office of Research Integrity; There, the investigation could take years.

Schrag also contacted Science. The journal presented the data to two independent image analysts, Elizabeth Bick and Jana Christopher, as well as Alzheimer’s researchers, including Selko; George Perry at the University of Texas, San Antonio; Donna Wilcock at the University of Kentucky, Lexington; and John Forsyth at the University of California, San Francisco. All agreed that there are real problems with the figures.

Piller also addressed earlier doubts about Lesne’s work. His postdoctoral supervisor, Denis Vivien of the University of Caen-Normandy, France, told Science that he and Lesne retracted a manuscript he co-wrote because of doubts about some of the immunostains, and others in his lab were unable to reproduce them.

Ash declined to comment on the allegations against Lesne, but stands by the science behind Aβ*56. “Scientists in our laboratories routinely and repeatedly detect Aβ*56 in a subset of Tg2576 and J20 mice,” he wrote to Alzforum (full comment below).

Ash’s group initially reported finding a type in human CSF; however, a subsequent paper suggested that this may be an artifact, with the bands possibly being confused with fragments of the N-terminal amyloid precursor protein (news March 2013; Grant et al., 2019). Another recent paper from the lab reported that the Aβ * 56 bands in previous publications may be an artifact of the use of the biotin-avidin system and/or protein A shedding from Sepharose beads (Grant et al., 2019).

Regardless of the impact of the allegations on Aβ*56 and oligomeric research, AD researchers view the field with a dark eye. “This is not a real scientific problem, but it is very unfortunate for the general scientific trust,” Selkoe wrote in Alzforum.

Others have pointed out that the scientific process produces results that cannot be reproduced. “I was very disappointed to read the article about possible ‘fake’ in this area. But science is self-correcting, and this is a good example,” wrote Colin Masters of the University of Melbourne in Australia to Alzforum (Madolyn Bowman Rogers).

News Citations

  1. Aβ A star is born? Oligomer Blamed for Memory Loss in APP Mice

  2. Aβ*56 found in human CSF, associated with Tau?

Therapy quotes

  1. simulation

Paper citations

  1. .
    Amyloid-beta protein dimers isolated directly from Alzheimer’s brain impair synaptic plasticity and memory..
    Nat Med. 2008 Aug;14(8):837-42.
  2. .
    Amyloid beta dimer-containing human CSF impairs synaptic plasticity: prevention of systemic passive immunization.
    J Neurosci. 2008 Apr 16;28(16):4231-7.
  3. .
    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. .
    Case in point: Endogenous biotinylated proteins and exogenously introduced protein induce antibody-independent artifacts in Western blot studies of brain-derived proteins..
    Biol Procedure Online. 2019;21:6. Epub April 18, 2019