Heena Cho | November 12th, 2024

“You can’t cheat to cure a disease. Biology doesn’t care.”  – Dr. Matthew Schrag of Vanderbilt University 

In 2006, neuroscientist Sylvain Lesné from the University of Minnesota Twin Cities (UMN) identified the main cause of Alzheimer’s, a devastating neurological disease affecting millions worldwide. Recent allegations on the validity of Lesné’s evidence, however, have cast serious doubt on this discovery, which has guided Alzheimer’s research for nearly two decades.

Amyloid plaques are abnormal clusters of protein in the brain that have been linked to Alzheimer’s since 1906. In 1984, a specific type of amyloid — amyloid-beta (Aβ) — was identified as the main component of these plaques. By the early 2000s, toxic subtypes of Aβ known to dissolve in certain bodily fluids were widely recognized as the primary cause of Alzheimer’s. These toxic subtypes appeared to impair communication between neurons, with higher levels found in people with Alzheimer’s compared to cognitively healthy individuals. Halting amyloid plaque buildup thus became the most promising and popular approach to treating Alzheimer’s. However, hundreds of subsequently administered amyloid-targeted therapies showed no promise, and by 2006, there were growing numbers of voices skeptical of the amyloid hypothesis.

Lesné’s paper was what rescued this waning theory. A recent graduate of the Ph.D. program at the University of Caen Normandy in France, Lesné was working under Dr. Karen Ashe, a physician and neuroscientist at UMN. Ashe was already renowned for her work with prions, infectious proteins that cause brain damage. Together, the duo discovered a previously unknown toxic subtype of amyloid, Aβ*56 (“amyloid-beta star 56”). Upon injecting Aβ*56 into young rats, their ability to recall simple, previously learned information diminished significantly. The findings were published in a 2006 Nature paper, garnering immediate attention and setting Lesné, the first author, on the road to stardom in Alzheimer’s research. In 2009, he joined UMN with his own NIH-funded lab, where Aβ*56 was his primary research focus. Lesné’s lab frequently used Western blots, a technique that detects specific proteins in samples. Lesné was solely responsible for assembling the Western blot images used in publications. 

Fast forward to August 2021. Dr. Matthew Schrag, a neuroscientist and physician at Vanderbilt, was asked to review claims regarding Simufilam, an experimental drug developed by Cassava Sciences to treat Alzheimer’s by improving cognition. A group of neuroscientists suspected that the research related to Simufilam was fraudulent and were suing Cassava Sciences. Schrag discovered that some published images about the drug and its mechanisms had indeed been altered or duplicated and reported these findings to the NIH. During this investigation, Schrag stumbled upon Lesné’s 2006 Nature paper and noticed red flags — potential fabrication in its published images.

Suspicions were raised, and a six-month investigation was launched by Science, casting doubt on hundreds of images in more than 70 of Lesné’s papers. Experts in image analysis and Alzheimer’s research agreed with Schrag’s findings. Elisabeth Bik, a forensic image consultant, commented that the published images seemed to have been pieced together from photos of different experiments. In academia, quantified results are obtained from experiments designed to test a hypothesis. To the shock and dismay of many, the 2006 landmark paper appears to have done the exact opposite, manipulating results from experiments to support a preconceived hypothesis.

Strangely enough, only a few other research groups have detected Aβ*56 since the duo’s discovery. Yet the Nature paper has been cited in approximately 2,300 scholarly articles. Research on Aβ continues to dominate the Alzheimer’s field, and in 2023 alone, NIH spent around $1.6 billion on projects mentioning amyloids — about half of its overall Alzheimer’s research funding.

What do Schrag’s findings mean? Is the amyloid hypothesis defunct?

Schrag’s findings do not entirely defunct the amyloid hypothesis. The concerns primarily target the Aβ field, and it is still possible that these proteins play a role in Alzheimer’s, since they are linked to cognitive impairment in animals.

However, nothing can account for the millions of dollars in wasted government funding and the misguided efforts of scientists and physicians. The scandal has broader implications beyond Alzheimer’s research, raising serious questions about the level of scrutiny applied to images by academic journals and granting institutions, which are meant to serve as gatekeepers. Submitted images often do not undergo sophisticated analysis, despite the availability of guidelines such as the Materials Design Analysis Reporting Framework (MDAR) for transparent reporting in the life sciences. Another significant concern is how this scandal will erode public trust in scientific research. What once seemed like solid evidence for a foundation of Alzheimer’s research has now been exposed as fraudulent. 

It is now up to researchers and the broader scientific community to correct cases of misconduct and strengthen preventive measures. Scientific integrity remains the cornerstone of any scientific research; upholding strict standards in academia will help maintain the trust necessary for advancing efforts to tackle complex diseases like Alzheimer’s.

References

Piller, C. (2022, July 21). Potential fabrication in research images threatens key theory of Alzheimer’s disease. Science. https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease

‌Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006). A specific amyloid-β protein assembly in the brain impairs memory. Nature, 440(7082), 352–357. https://doi.org/10.1038/nature04533

Macleod, M., Collings, A. M., Graf, C., Kiermer, V., Mellor, D., Swaminathan, S., Sweet, D., & Vinson, V. (2021). The MDAR (Materials Design Analysis Reporting) Framework for transparent reporting in the life sciences. Proceedings of the National Academy of Sciences, 118(17). https://doi.org/10.1073/pnas.2103238118

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