For more than 15 years, much of the Alzheimer’s Disease establishment has focused its attention—and hundreds of millions of research dollars—on the theory that the disease primarily is caused by the build-up of plaque, called amyloid beta, in the brain. But what if that theory is based on flawed data?
A six-month investigation by Charles Piller, an award-winning reporter for Science magazine, finds that key research published in 2006 may have included fabricated data. The 2006 paper, published in the journal Nature, identified a subtype of amyloid called Aβ*56 as a cause of Alzheimer’s. That paper has been cited nearly 2,300 times, suggesting how many scientists spent time focusing their own work on this theory.
The National Institute of Health may have provided as much as $280 million in drug research funding based on the theory. Pharmaceutical companies may have spent billions of dollars of their own money, much subsidized by federal tax benefits. Advocacy groups such as the Alzheimer’s Association aggressively promoted it, lobbied for more funding dollars to advance it, and pushed FDA to approve drugs that aim to reduce this material in the brain.
Most troubling of all, because the hypothesis so dominated Alzheimer’s research in recent years, it has choked off funding for those investigating other potential causes of the disease. That means that for over a decade, even as cases of Alzheimer’s increase, precious research time has been lost and opportunities for finding effective treatments missed.
During the past 15 years, scores of anti-Alzheimer’s drug trials based on the amyloid beta theory have failed.
The controversial research was published by Sylvain Lesné of the University of Minnesota (UMN), Twin Cities. At the time, Lesné was a new PhD hired by the lab run by Karen Ashe, a highly-regarded neuroscientist and Alzheimer’s researcher.
His pathbreaking paper purported to show Aβ*56 caused dementia in rats. Lesné won academic prizes and this year received a five-year NIH grant to continue his research. Most important, his paper was the foundation for scores, if not hundreds, of studies that may have followed his research down a blind alley.
How influential is his work? Very. One example: The controversial drug Aduhelm, approved last year by the FDA, was aimed at breaking down amyloid beta. Indeed, in a highly unusual step the FDA approved the drug explicitly to further amyloid beta research even though it acknowledged there was little direct evidence Aduhelm provided any clinical benefit to people with Alzheimer’s.
For years, a handful of scientists questioned Lesné’s results. But few in the Alzheimer’s establishment paid attention. In 2021, Matthew Schrag, a neuroscientist and physician at Vanderbilt University, was hired by a lawyer representing two “short-seller” investors to investigate claims by a maker of an experimental Alzheimer’s drug. That led him to dig into Lesné’s original research.
While Schrag did not accuse the researcher of misconduct, the evidence that data were manipulated appears strong.
A website called PubPeer, where scientists question published results of others, also found problems with Lesné’s data. But the questions went far beyond online sleuths. Piller reported concerns raised by several highly-regarded Alzheimer’s researchers, including Harvard University’s Dennis Selkoe, a well-known proponent of the amyloid theory.
Piller found scientists have been unable to replicate Lesné’s work, a critical step in all research. Indeed, after 15 years, few have even been able to even detect Aβ*56 in human tissue.
On July 14, Nature added a note to Lesné’s original article: “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.”
Lesné did not respond to requests for comment from Science. The University of Minnesota says it is investigating the claims. In an email to Science, Ashe called Piller’s story “sobering.” But she wrote, “I still have faith in Aβ*56,” adding that on-going research “has the potential to explain why Aβ therapies may yet work despite recent failures targeting amyloid plaques.”
She may be right. Piller was careful to report that while Lesné’s published data may be questionable, or may even have been manipulated, it remains possible that amyloid beta is at least a partial cause of Alzheimer’s Disease. And a drug that prevents the build-up of these proteins could yet help slow the progression of Alzheimer’s.
But the Science investigation, following so many failed amyloid beta drug trials, suggests a colossal scientific failure that may have led to needless suffering by those living with Alzheimer’s Disease and their family members.
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