Leading Alzheimer’s theory undermined: Did tampering waste 16 years of research?

Hundreds of millions of dollars and years of research across an entire field may have been wasted due to potentially falsified data that helped lay the foundation for the leading hypothesis of what causes Alzheimer’s disease.

The allegations centre around a landmark 2006 study — a paper which has been cited nearly 2,300 times — whose findings identify a protein called amyloid beta as a cause of Alzheimer’s. Since then, the hypothesis that sticky deposits of amyloid beta form plaques in the brain that slow cognition has dominated Alzheimer’s research and treatment development.

But a six-month investigation by Science magazine has revealed that the data backing up this influential study may have been doctored, potentially leading scientists down the wrong road for 16 years.

The controversial research was authored by Sylvain Lesné from the University of Minnesota, who at the time was a new PhD student working under the highly-regarded Alzheimer’s researcher Karen Ashe.

Lesné’s paper purported to show that a specific subtype of amyloid beta (Aβ*56) caused dementia in rats and was hailed as a major breakthrough — bringing awards, funding and notoriety to its authors, but also breathing new life into the amyloid beta theory.

In the U.S., Science found that the National Institute of Health (NIH) went from directing zero dollars for amyloid-related Alzheimer’s research in 2006, when Lesné’s research was published, to US$287 million in 2021.

A handful of scientists doubted the results of Lesné’s research but it wasn’t until 2021 when Matthew Schrag, a neuroscientist and physician from Vanderbilt University, dug deeper and found evidence that Lesné’s findings weren’t all they appeared to be.

While visiting PubPeer, a website where scientists flag possible errors in peer-reviewed research, Schrag came across postings that questioned the authenticity of some of Lesné’s graphs showing amyloid beta concentration levels. The images showed evidence of tampering and duplication, with some results seemingly cut and pasted to appear stronger.

Schrag launched his own investigation into Lesné’s work and found evidence of image tampering in some 20 papers.

In a whistleblower report to NIH, Schrag wrote that his findings represent only “a fraction of the anomalies easily visible on review of the publicly accessible data.”

He added that Lesné’s work “not only represents a substantial investment in (NIH) research support, but has been cited … thousands of times and thus has the potential to mislead an entire field of research.”

Nobel laureate Thomas Südhof agrees, saying in an interview with Science that Lesné’s paper provided an “important boost” to the amyloid hypothesis at a time when scientists were beginning to direct their attention elsewhere.

“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,” the Stanford neuroscientist said.

On July 14 of this year, Nature added a warning to Lesné’s 2006 study, writing, “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.”

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Lesné so far has not made any public comment on the allegations, but the University of Minnesota says it is investigating the claims.

The Alzheimer Society of Canada (ASC), which has distributed $67 million in grants for Alzheimer’s research since its inception, issued a public statement regarding the allegations, saying they are monitoring the situation.

In a statement to Global News, Saskia Sivananthan, chief of research, knowledge transfer and exchange for the ASC wrote, “The recent news of potential research misconduct is serious and requires further inquiry, however, it is important that all dementia research should not be painted with the same broad brush of these allegations given how large and diverse the field of dementia research is.”

“There is no doubt that the amyloid beta hypothesis had an impact on the direction of dementia research throughout the world, however, again, it is important to note that amyloid beta is one of a large number of hypotheses that researchers are studying to understand the possible causes of dementia right now,” Sivananthan added.

Gerold Schmitt-Ulms, a University of Toronto professor at the Tanz Centre for Research in Neurodegenerative Disease, echoed their sentiments, saying that while the allegations of misconduct are credible, he’s more worried about what implications this has for the loss of public trust in Alzheimer’s research.

“It is neither new nor surprising that a small number of individuals in the sciences resort to fraudulent activity because the short-term gain, measured in research funding or career advancement, can be considerable,” he wrote to Global News. “Fortunately, in this case, the implications for (Alzheimer’s disease) research are minor.”

According to Schmitt-Ulms, the direction of Alzheimer’s research is unlikely to fundamentally change in light of these allegations because so much is still unknown about the early stages of the disease.

“Most research groups in Canada no longer focus on (amyloid beta) but anybody studying (Alzheimer’s disease) is well advised to not ignore this molecule either,” he said.

Even still, the ASC concedes that Lesné’s potential misconduct is worrying, writing that “any potential diversion of money or time is a cause for concern,” given that dementia costs the Canadian economy more than $10.4 billion annually.

While it’s impossible to know the true losses to Alzheimer’s research if Lesné did indeed falsify his data, it’s hard to ignore that the only Alzheimer’s drug that has come to market in North America is a treatment that targets amyloid beta.

Aduhelm, a drug developed by Biogen, recently received approval from the U.S. Food and Drug Administration despite little clinical evidence that it benefits those who suffer from Alzheimer’s. The drug was controversially fast-tracked through the approval process in order to further amyloid beta research.

The drug was initially submitted for approval from Health Canada but was withdrawn by the company.

Despite the increased scrutiny on amyloid beta, Schmitt-Ulms hasn’t given up on the protein, or drugs that combat it, saying “The door toward (anti-amyloid beta) therapies should not be closed.”

“There also exists the possibility that a combination therapy targeting the accumulation of aberrant (amyloid beta) and something else may prove to be effective.”