{"id":3962,"date":"2022-08-05T07:03:03","date_gmt":"2022-08-05T07:03:03","guid":{"rendered":"https:\/\/www.editage.com\/insights\/image-fabrication-controversy-in-alzheimers-research-threatens-a-fundamental-hypothesis\/"},"modified":"2025-11-25T16:34:07","modified_gmt":"2025-11-25T11:04:07","slug":"image-fabrication-controversy-in-alzheimers-research-threatens-a-fundamental-hypothesis","status":"publish","type":"post","link":"https:\/\/www.editage.com\/insights\/image-fabrication-controversy-in-alzheimers-research-threatens-a-fundamental-hypothesis","title":{"rendered":"Image fabrication controversy in Alzheimer\u2019s research threatens a fundamental hypothesis"},"content":{"rendered":"

On July 21, 2022, the prominent blog Retraction Watch1<\/span><\/sup> and esteemed American journal Science<\/i>2<\/span><\/sup> published articles on the newly uncovered evidence of potential academic misconduct in Alzheimer\u2019s 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.<\/span><\/span><\/span><\/p>\n

Here, I present a concise overview of the controversy and what it means for the field.<\/span><\/span><\/span><\/p>\n

The amyloid hypothesis and controversy\u2013a timeline<\/span><\/span><\/span><\/span><\/span><\/h1>\n

Background<\/span><\/span><\/span><\/span><\/span><\/h2>\n
    \n
  • \n

    1906<\/b> Alois Alzheimer describes AD, noting the progressive development of plaques in the brain, concurrent with cognitive decline3<\/span><\/sup>.<\/span><\/span><\/span><\/p>\n<\/li>\n

  • \n

    1984 <\/b>Glenner and Wong determine the plaques to be primarily composed of amyloid-beta (A\u03b2)4<\/span><\/sup>.<\/span><\/span><\/span><\/p>\n<\/li>\n

  • \n

    1991<\/b> Goate et al. find that a mutation in the amyloid precursor protein gene causes familial AD, providing critical evidence for the amyloid hypothesis5<\/span><\/sup>.<\/span><\/span><\/span><\/p>\n<\/li>\n

  • \n

    1990s <\/b>onward<\/b> Many researchers seek to develop A\u03b2-targeting therapies to prevent the progression of AD, but most candidates fail to produce results. Alternative hypotheses gain ground6<\/span><\/sup>.<\/span><\/span><\/span><\/p>\n<\/li>\n<\/ul>\n

    A\u03b2*56: a new star<\/span><\/span><\/span><\/span><\/span><\/h2>\n
      \n
    • 2006 <\/b>Neuroscientists Karen Ashe and Sylvain Lesn\u00e9 make a groundbreaking discovery: A\u03b2*56, an A\u03b2 oligomer unknown until then, can induce characteristic symptoms of cognitive decline in mice7<\/span><\/sup>. Strikingly, even injecting this purified oligomer can induce such changes. The amyloid hypothesis is bolstered by this finding.<\/span><\/span><\/span><\/li>\n
    • 2006 onward<\/b> The paper by Lesn\u00e9 et al. becomes one of the most cited publications on Alzheimer\u2019s disease.<\/span><\/span><\/span><\/li>\n
    • 2009<\/b> Sylvain Lesn\u00e9 is offered his own laboratory at the University of Minnesota, which receives significant NIH funding over the years8<\/span><\/sup>.<\/span><\/span><\/span><\/li>\n
    • 2009 onwards<\/b> Lesn\u00e9 continues to publish many articles on A\u03b2, particularly with his collaborators Karen Ashe and Matthew Sherman.<\/span><\/span><\/span><\/li>\n<\/ul>\n

      Questions emerge<\/span><\/span><\/span><\/span><\/span><\/h2>\n
        \n
      • Late 2021 <\/b>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 Lesn\u00e9 et al9<\/span><\/sup>. This attracts the attention of Matthew Schrag.<\/span><\/span><\/span><\/li>\n
      • Early 2022<\/b> Schrag, Elisabeth Bik (a scientific integrity consultant), and anonymous PubPeer users note more evidence of image manipulation in the work of Lesn\u00e9 and Ashe, including in their groundbreaking 2006 paper. Schrag makes his concerns known to the NIH and journals, including Nature<\/i>2<\/span><\/sup>.<\/span><\/span><\/span><\/li>\n
      • July 2022<\/b><\/span><\/span><\/span>\n
          \n
        • Nature<\/i> publishes a warning on the online version of the 2006 article, stating that they are investigating issues with the images7<\/span><\/sup>. <\/span><\/span><\/span><\/li>\n
        • Science Signaling<\/i> publishes editorial expressions of concern on two articles from 201610<\/span><\/sup> and 201711<\/span><\/sup> that are co-authored by Lesn\u00e9 and Sherman. <\/span><\/span><\/span><\/li>\n
        • The Journal of Neuroscience<\/i>12<\/span><\/sup> and Brain<\/i>13<\/span><\/sup> issue corrections.<\/span><\/span><\/span><\/li>\n
        • Lesn\u00e9 and Sherman have so far declined to comment. <\/span><\/span><\/span><\/li>\n
        • The NIH have also declined to comment.<\/span><\/span><\/span><\/li>\n
        • Ashe has addressed some concerns regarding the figures on PubPeer14<\/span><\/sup>. She has also attempted to retract her Nature <\/i>paper15<\/span><\/sup>.<\/span><\/span><\/span><\/li>\n<\/ul>\n<\/li>\n<\/ul>\n

          The next steps<\/span><\/span><\/span><\/span><\/span><\/h1>\n

          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 Lesn\u00e9 and colleagues will face mounting scrutiny and questions about the future of their careers.<\/span><\/span><\/span><\/p>\n

          One crucial issue is that the very existence of A\u03b2*56 has been further brought into question. Some researchers have already shared concerns about the A\u03b2*56 oligomer, with some failing to replicate the findings2<\/span><\/sup>. The current controversy once again casts serious doubts over the veracity of findings related to A\u03b2*56. It will be vital for future research efforts to clarify the status of A\u03b2*56 and confirm hitherto published findings.<\/span><\/span><\/span><\/p>\n

          What this means for the field<\/span><\/span><\/span><\/span><\/span><\/h1>\n

          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<\/span><\/sup>. 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<\/span><\/sup>, have been marred by controversy. Once again, a reductive model of AD focusing on A\u03b2 alone seems misguided.<\/span><\/span><\/span><\/p>\n

          However, A\u03b2 plaques without doubt are still part of AD pathogenesis. Future studies and drug candidates may need to consider A\u03b2 less as a causative agent and more as a product generated downstream of other biochemical changes.<\/span><\/span><\/span><\/p>\n

          More broadly, this development is another major example of the ongoing reproducibility crisis in science. Much like how researchers failed to replicate Haruko Obokata\u2019s findings on induced pluripotent stem cells18<\/span><\/sup>, this unfolding controversy may dramatically end some promising careers and bring many more findings into question.<\/span><\/span><\/span><\/p>\n

          References<\/span><\/span><\/span><\/span><\/span><\/h1>\n

          1.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Marcus, A. A. Papers on Alzheimer\u2019s slapped with expressions of concern. Retraction Watch<\/i> https:\/\/retractionwatch.com\/2022\/06\/21\/papers-on-alzheimers-slapped-with-expressions-of-concern\/ (2022).<\/span><\/span><\/span><\/p>\n

          2.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Potential fabrication in research images threatens key theory of Alzheimer\u2019s disease. https:\/\/www.science.org\/content\/article\/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease.<\/span><\/span><\/span><\/p>\n

          3.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Hippius, H. & Neund\u00f6rfer, G. The discovery of Alzheimer\u2019s disease. Dialogues Clin. Neurosci.<\/i> 5<\/b>, 101\u2013108 (2003).<\/span><\/span><\/span><\/p>\n

          4.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Glenner, G. G. & Wong, C. W. Alzheimer\u2019s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun.<\/i> 120<\/b>, 885\u2013890 (1984).<\/span><\/span><\/span><\/p>\n

          5.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Goate, A. et al.<\/i> Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease. Nature<\/i> 349<\/b>, 704\u2013706 (1991).<\/span><\/span><\/span><\/p>\n

          6.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Castello, M. A. & Soriano, S. On the origin of Alzheimer\u2019s disease. Trials and tribulations of the amyloid hypothesis. Ageing Res. Rev.<\/i> 13<\/b>, 10\u201312 (2014).<\/span><\/span><\/span><\/p>\n

          7.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Lesn\u00e9, S. et al.<\/i> A specific amyloid-\u03b2 protein assembly in the brain impairs memory. Nature<\/i> 440<\/b>, 352\u2013357 (2006).<\/span><\/span><\/span><\/p>\n

          8.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 New NIH Funding! | The Lesn\u00e9 Laboratory. https:\/\/lesnelab.org\/2019\/08\/23\/new-nih-funding-2\/ (2019).<\/span><\/span><\/span><\/p>\n

          9.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 PubPeer – Search publications and join the conversation. https:\/\/pubpeer.com\/search?q=lesne.<\/span><\/span><\/span><\/p>\n

          10.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Alfonso, S. I. et al.<\/i> Gain-of-function mutations in protein kinase C\u03b1 (PKC\u03b1) may promote synaptic defects in Alzheimer\u2019s disease. Sci. Signal.<\/i> 9<\/b>, ra47\u2013ra47 (2016).<\/span><\/span><\/span><\/p>\n

          11.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 The amyloid-\u03b2 oligomer A\u03b2*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. https:\/\/www.science.org\/doi\/10.1126\/scisignal.aal2021.<\/span><\/span><\/span><\/p>\n

          12.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Larson, M. E. et al.<\/i> Soluble \u03b1-Synuclein Is a Novel Modulator of Alzheimer\u2019s Disease Pathophysiology. J. Neurosci.<\/i> 32<\/b>, 10253\u201310266 (2012).<\/span><\/span><\/span><\/p>\n

          13.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Brain amyloid-\u03b2 oligomers in ageing and Alzheimer\u2019s disease | Brain | Oxford Academic. https:\/\/academic.oup.com\/brain\/article\/136\/5\/1383\/285958?login=false.<\/span><\/span><\/span><\/p>\n

          14.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 PubPeer – A specific amyloid-beta protein assembly in the brain impair… https:\/\/pubpeer.com\/publications\/8FF7E6996524B73ACB4A9EF5C0AACF.<\/span><\/span><\/span><\/p>\n

          15.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Weintraub, K. A. and K. Investigation into pivotal Alzheimer\u2019s study raises questions on suspected disease culprit. USA TODAY<\/i> https:\/\/www.usatoday.com\/story\/news\/health\/2022\/07\/29\/alzheimers-theory-scrutinized-accusation-fabricated-research\/10142926002\/.<\/span><\/span><\/span><\/p>\n

          16.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Faked Beta-Amyloid Data. What Does It Mean? https:\/\/www.science.org\/content\/blog-post\/faked-beta-amyloid-data-what-does-it-mean.<\/span><\/span><\/span><\/p>\n

          17.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Simufilam | ALZFORUM. https:\/\/www.alzforum.org\/therapeutics\/simufilam.<\/span><\/span><\/span><\/p>\n

          18.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Marcus, A. A. Fourth retraction for Haruko Obokata, focus of STAP cell scandal, after Harvard investigation. Retraction Watch<\/i> https:\/\/retractionwatch.com\/2020\/02\/13\/fourth-retraction-for-haruko-obokata-focus-of-stap-cell-scandal-after-harvard-investigation\/ (2020).<\/span><\/span><\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

          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\u2019s 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 […]<\/p>\n","protected":false},"author":2681,"featured_media":33313,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"categories":[2398,2418],"tags":[99,2581],"new_categories":[],"new_tags":[],"series":[],"class_list":["post-3962","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-ethical-declarations","category-research-ethics","tag-ethical-guidelines","tag-ethics-of-research"],"acf":[],"yoast_head":"\nImage fabrication controversy in Alzheimer\u2019s research threatens a fundamental hypothesis<\/title>\n<meta name=\"description\" content=\"On July 21, 2022, the prominent blog Retraction Watch\u00a0and esteemed American journal Science\u00a0published articles on the newly uncovered evidence of potential academic misconduct in Alzheimer\u2019s disease (AD) research. 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