2022-07-26| Special

Billions of Research Dollars May Have Been Wasted Due to Fraudulent Alzheimer’s Study

by Reed Slater
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A popular study, originally published in 2006, claiming Alzheimer’s is likely caused by the buildup of the protein amyloid beta (Aβ) in the brain, is under scrutiny by the scientific community for potentially falsifying images and results of the study. The implications of tampered findings could significantly impact the industry, which has predicated most research and development on the notion that plaque buildup consisting of Aβ is the driving factor in Alzheimer’s. 

Since Nature initially published the study, the National Institute of Health (NIH) has granted billions of dollars to institutions for Alzheimer’s research, primarily driven by the idea that the field has gained a better understanding of the underlying causes of the disease. Dozens of companies are working on anti-Aβ treatment options, all of which may have to undergo a momentous shift if authorities confirm the authors falsified their findings.


The Potential Discovery of the Century


Alzheimer’s is a devastating disease that affects more than 5 million people in the US alone and has remained mysterious to researchers for years due to a lack of understanding of the underlying causes of the disease. Hundreds of researchers tried to determine the source of Alzheimer’s to tailor treatment options for those living with it. So many tried in vain until Sylvain Lesné, a French neuroscientist, co-authored the fateful paper with Karen Ashe that is the subject of biotech’s biggest scandal.

The paper claims that a specific Aβ oligomer called Aβ*56 may be responsible for cognitive decline associated with Alzheimer’s. Aβ-derived plaque buildup in the brain has been a likely culprit as the cause of Alzheimer’s since the 1980s. However, research around the subject had grown stagnant, prompting many to wonder if they had been betting on the wrong horse. That was until Lesné and Ashe’s study pinpointed a specific element to go after, spearheading a renewed interest in Aβ-focused research and treatment development. 

Ashe and Lesné quickly gained notoriety, as did the paper itself. Lesné rode the wave while publishing several other papers and starting his own NIH-funded lab at the University of Minnesota Twin Cities, with Aβ*56 as his primary research focus. Lesné even received a five-year grant from the NIH in May this year, providing over $750,000 for 2022 alone. 

All the hype behind the authors and the paper was so exciting for the industry, which desperately continued looking for treatment options for Alzheimer’s. The report is one of the most cited Alzheimer’s papers, with nearly 2,300 citations. Now, though, the paper comes with a disclaimer.

The editors of Nature have been alerted to concerns regarding some of the figures in this paper. Nature is investigating these concerns, and a further editorial response will follow as soon as possible. In the meantime, readers are advised to use caution when using results reported therein.” 

All the hope the paper promised for an area in desperate need of advancement could be shot down after inquisitive industry experts pointed out critical flaws in the study. 


Related Article: Eisai and Biogen’s New Alzheimer’s Drug to Receive FDA Decision by January


Manipulating Images to Better Fit a Hypothesis


Criticisms of Lesné’s work date back to 2013, when an anonymous user pointed out concerns about one of Lesné’s papers on the scientific research and review forum, PubPeer. The commenter questioned the authenticity of the blots; images used to detect the presence of proteins used in the 2012 paper, suggesting that the authors may have altered images to falsify findings of the Aβ*56 protein.

Six years later, Dutch microbiologist and notable photo manipulation analyst Elisabeth M Bik responded to the anonymous user with some incriminating evidence, validating their concerns. Bik annotated and marked two images from the paper highlighting suspicious areas that may have been tampered with, suggesting the images may have included duplicates but still providing authors the opportunity to respond. 

Bik’s analysis of suspected photo manipulation from a 2012 paper with Lesné listed as a primary author.
Bik’s analysis of suspected photo manipulation from a 2012 paper with Lesné listed as a primary author.

Though the early criticisms were concerning, the matter remained silent for several years until another skeptic neuroscientist rehashed the issue. Matthew Schrag, an assistant professor of neurology at Vanderbilt University, went public with his concerns about Lesné and Ashe’s work after criticizing the controversial FDA approval of Aduhelm and his involvement with another Alzheimer’s-related research scandal. 

Schrag initially involved himself in a petition requesting to halt clinical trials of an Alzheimer’s drug developed by Cassava Sciences called Simufilam, citing that some research surrounding the drug may be fraudulent. In doing more research to support his case against Cassava, Shrag stumbled upon some of the suspicions around Lesné’s Alzheimer’s research, prompting Schrag to investigate on his own. 

In his investigation, Schrag found many of the same discrepancies others had revolving around Lesné’s work, most notably image manipulation of potentially duplicated proteins. However, Schrag insists that his findings are not definitive and that he can only work with images published in the papers. For a more thorough investigation, it will be necessary for the proper authorities to gain access to all original photos from the studies to assess the possibility of image manipulation further. 

Since the scandal skyrocketed into public discourse this month, several dozen other curious scientists have added to the piles of potential evidence against Lesné and Ashe in their Aβ-focused papers. Additionally, several institutions are performing independent investigations like Science and Nature. Schrag filed a whistleblower report with the NIH, which the government organization said would pass on any credible complaints to the Department of Health and Human Services Office of Research Integrity for review. 


Implications of Duping the Scientific Community


Falsifying data and research is a major offense within the scientific community. The case of Lesné and Ashe is exceptional because it went so long without being noticed and prompted a revival in the amyloid hypothesis surrounding Alzheimer’s research. 

Biogen and Eisai developed the world’s first Alzheimer’s treatment in decades, Aduhelm, and designed and evaluated it based on plaque buildup due to Aβ as the driving force for Alzheimer’s. The two companies have a very similar drug utilizing the same mechanism and biomarkers scheduled for an FDA decision in January next year. 

Aduhelm continues to receive criticism for its lack of positive performance and potentially fatal side effects. Now, to think that Aduhelm’s disappointing rollout could have been influenced by a flawed paper published over 15 years ago is disconcerting. 

The scandal might not be the end for anti-Aβ treatments; decades of research show an association between plaque buildup in the brain and Alzheimer’s. With that said, if the remaining anti-Aβ Phase 3 trials come up empty as most previous ones have, the amyloid hypothesis will surely sink along with the billions of dollars invested in it. 

Further developments from various investigations will unfold in the coming months and probably years, but the effects will linger even longer. Until then, the case serves as a stark reminder for the scientific community to remain vigilant. While most scientists and researchers have pure motives, there will inevitably be a few that do not. It is the community’s responsibility at all levels to maintain the sanctity of scientific development and further humanity for the better. 

Related Article:
Are Memory Loss in Alzheimer’s Disease Related to Changes in Blood Vessels in the Brain?
Roche Bags Fast Track Label for New Alzheimer’s Diagnostic

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