On July 21, 2022, the prominent blog Retraction Watch¹ and esteemed American journal Science² published articles on the newly uncovered evidence of potential academic misconduct in Alzheimer’s disease (AD) research, introducing the controversy to a large audience. The controversies were revealed in part by the image analyses of Dr. Matthew Schrag of Vanderbilt University. His analyses have cast shadows on several careers and may lead to dozens of retractions. They even jeopardize one of the key theories underlying our current assumptions about the pathogenesis of AD.

Here, I present a concise overview of the controversy and what it means for the field.

The amyloid hypothesis and controversy–a timeline

Background

• 1906 Alois Alzheimer describes AD, noting the progressive development of plaques in the brain, concurrent with cognitive decline³.

• 1984 Glenner and Wong determine the plaques to be primarily composed of amyloid-beta (Aβ)⁴.

• 1991 Goate et al. find that a mutation in the amyloid precursor protein gene causes familial AD, providing critical evidence for the amyloid hypothesis⁵.

• 1990s onward Many researchers seek to develop Aβ-targeting therapies to prevent the progression of AD, but most candidates fail to produce results. Alternative hypotheses gain ground⁶.

Aβ*56: a new star

• 2006 Neuroscientists Karen Ashe and Sylvain Lesné make a groundbreaking discovery: Aβ*56, an Aβ oligomer unknown until then, can induce characteristic symptoms of cognitive decline in mice⁷. Strikingly, even injecting this purified oligomer can induce such changes. The amyloid hypothesis is bolstered by this finding.
• 2006 onward The paper by Lesné et al. becomes one of the most cited publications on Alzheimer’s disease.
• 2009 Sylvain Lesné is offered his own laboratory at the University of Minnesota, which receives significant NIH funding over the years⁸.
• 2009 onwards Lesné continues to publish many articles on Aβ, particularly with his collaborators Karen Ashe and Matthew Sherman.

Questions emerge

• Late 2021 Anonymous users of PubPeer, an online platform for reviews and discussions on published research, notice evidence of image manipulation in a 2016 paper published by Lesné et al⁹. This attracts the attention of Matthew Schrag.
• Early 2022 Schrag, Elisabeth Bik (a scientific integrity consultant), and anonymous PubPeer users note more evidence of image manipulation in the work of Lesné and Ashe, including in their groundbreaking 2006 paper. Schrag makes his concerns known to the NIH and journals, including Nature².
• July 2022
  • Nature publishes a warning on the online version of the 2006 article, stating that they are investigating issues with the images⁷.
  • Science Signaling publishes editorial expressions of concern on two articles from 2016¹⁰ and 2017¹¹ that are co-authored by Lesné and Sherman.
  • The Journal of Neuroscience¹² and Brain¹³ issue corrections.
  • Lesné and Sherman have so far declined to comment.
  • The NIH have also declined to comment.
  • Ashe has addressed some concerns regarding the figures on PubPeer¹⁴. She has also attempted to retract her Nature paper¹⁵.

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The next steps

At the time of writing, no decisions were made regarding the careers and funding of the people involved in this controversy, and no official retractions have been made. However, without remarkable exculpatory evidence, it seems likely that Lesné and colleagues will face mounting scrutiny and questions about the future of their careers.

One crucial issue is that the very existence of Aβ*56 has been further brought into question. Some researchers have already shared concerns about the Aβ*56 oligomer, with some failing to replicate the findings². The current controversy once again casts serious doubts over the veracity of findings related to Aβ*56. It will be vital for future research efforts to clarify the status of Aβ*56 and confirm hitherto published findings.

What this means for the field

Despite almost forty years of research on the molecular underpinnings of AD, its etiology and pathogenesis remain obscure, and very little progress in preventing and treating AD has been made¹⁶. The amyloid hypothesis has long been widely accepted as a major explanation for the etiology of AD, but billions of dollars of grants and hundreds of candidate drugs investigated have failed to uncover an effective treatment, and some drugs that have been brought to market, such as simufilam¹⁷, have been marred by controversy. Once again, a reductive model of AD focusing on Aβ alone seems misguided.

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However, Aβ plaques without doubt are still part of AD pathogenesis. Future studies and drug candidates may need to consider Aβ less as a causative agent and more as a product generated downstream of other biochemical changes.

More broadly, this development is another major example of the ongoing reproducibility crisis in science. Much like how researchers failed to replicate Haruko Obokata’s findings on induced pluripotent stem cells¹⁸, this unfolding controversy may dramatically end some promising careers and bring many more findings into question.

References

1.            Marcus, A. A. Papers on Alzheimer’s slapped with expressions of concern. Retraction Watch https://retractionwatch.com/2022/06/21/papers-on-alzheimers-slapped-with-expressions-of-concern/ (2022).

2.            Potential fabrication in research images threatens key theory of Alzheimer’s disease. https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease.

3.            Hippius, H. & Neundörfer, G. The discovery of Alzheimer’s disease. Dialogues Clin. Neurosci. 5, 101–108 (2003).

4.            Glenner, G. G. & Wong, C. W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).

5.            Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).

6.            Castello, M. A. & Soriano, S. On the origin of Alzheimer’s disease. Trials and tribulations of the amyloid hypothesis. Ageing Res. Rev. 13, 10–12 (2014).

7.            Lesné, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).

8.            New NIH Funding! | The Lesné Laboratory. https://lesnelab.org/2019/08/23/new-nih-funding-2/ (2019).

9.            PubPeer - Search publications and join the conversation. https://pubpeer.com/search?q=lesne.

10.          Alfonso, S. I. et al. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease. Sci. Signal. 9, ra47–ra47 (2016).

11.          The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. https://www.science.org/doi/10.1126/scisignal.aal2021.

12.          Larson, M. E. et al. Soluble α-Synuclein Is a Novel Modulator of Alzheimer’s Disease Pathophysiology. J. Neurosci. 32, 10253–10266 (2012).

13.          Brain amyloid-β oligomers in ageing and Alzheimer’s disease | Brain | Oxford Academic. https://academic.oup.com/brain/article/136/5/1383/285958?login=false.

14.          PubPeer - A specific amyloid-beta protein assembly in the brain impair... https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0AACF.

15.          Weintraub, K. A. and K. Investigation into pivotal Alzheimer’s study raises questions on suspected disease culprit. USA TODAY https://www.usatoday.com/story/news/health/2022/07/29/alzheimers-theory-scrutinized-accusation-fabricated-research/10142926002/.

16.          Faked Beta-Amyloid Data. What Does It Mean? https://www.science.org/content/blog-post/faked-beta-amyloid-data-what-does-it-mean.

17.          Simufilam | ALZFORUM. https://www.alzforum.org/therapeutics/simufilam.

18.          Marcus, A. A. Fourth retraction for Haruko Obokata, focus of STAP cell scandal, after Harvard investigation. Retraction Watch https://retractionwatch.com/2020/02/13/fourth-retraction-for-haruko-obokata-focus-of-stap-cell-scandal-after-harvard-investigation/ (2020).