Scientific Community Questions Anti-Amyloid Theory - the Basis for Seminal Alzheimer's Work
The data used to support the argument that Aβ*56 - an oligomer of amyloid-β proteins - is responsible for the Alzheimer’s Disease hallmark of memory loss appears to have been fabricated or heavily tampered with, according to an investigation published Thursday by the scientific journal Science.
If proven true, this could set the field back by nearly two decades and could mean millions of dollars have been spent chasing after an unreliable disease culprit.
The allegations of misconduct stem from the scientific sleuthing of Matthew Schrag, a neuroscientist and physician at Vanderbilt University. The 37-year-old doctor’s claims rest on allegedly tampered images of Western blots, a laboratory technique used to visualize proteins.
Close examination of these photos revealed that bands were cut-and-pasted, or manipulated in other ways, to suggest that levels of Aβ*56 increased with age and in conjunction with dementia symptoms. (Schrag’s investigations into the possible Aβ*56 misconduct are not connected with this work at Vanderbilt).
At the center of the misconduct allegations are Sylvain Lesné and Karen Ashe. Their seminal 2006 paper, published in the leading medical journal Nature, was the first to identify Aβ*56, which the researchers found to accumulate in the brains of older mice.
In the study, injecting the toxic oligomer into young mice dramatically compromised their memory, further suggesting that Aβ*56 was involved in the memory loss in Alzheimer’s. As of July 14, Nature has begun investigating concerns regarding the allegations of evidence tampering in this paper.
But in the 16 years since, Lesné and Ashe’s paper has been cited by some 2,300 other studies. Now under a long shadow of a doubt, their findings helped establish amyloid oligomer research in Alzheimer’s disease. In 2021, this field received nearly $300 million in support from the National Institutes of Health.
“The immediate, obvious damage is wasted NIH funding and wasted thinking in the field because people are using these results as a starting point for their own experiments,” Thomas Südhof, a neuroscientist at Stanford University, Nobel laureate and an expert in Alzheimer’s told Science.
A Fraught Field
Since amyloid-β was first discovered to accumulate in the brains of Alzheimer’s patients in the early 1990s, pharma companies have been using it as a target for potential therapies. None have so far succeeded.
In June 2021, Biogen’s Aduhelm (aducanumab) became the first-ever drug approved by the United States Food and Drug Administration for the treatment of Alzheimer’s. Even as it took decades for the field to see the treatment through to the market, Aduhelm was met with strong controversy. Many skeptics said its efficacy data were questionable and its risk-benefit trade-off was a bit too undesirable.
The company was ultimately forced to abandon the post-market real-world study for Aduhelm after insurers drastically limited their coverage of the drug, but a Phase IV confirmatory trial will push through.
Cassava Sciences, another player in the Alzheimer’s space, has also seen its share of controversy. Last month, Springer retracted a study that was written by a key collaborator working with the company.
Springer reported the study about Cassava’s Alzheimer’s candidate simufilam was riddled with concerns about doctored Western blot images. In April, it also came to light that the journal PLoS One had retracted five simufilam studies, all written by the same collaborator that authored the Springer paper. Schrag was first investigating claims of Cassava’s scientific misconduct when he stumbled upon the 2006 Nature paper about Aβ*56.