The scientific method, which serves as the modern approach to acquiring knowledge, is based on careful observation while applying rigorous skepticism about what is observed. This skepticism is needed because cognitive assumptions can distort how we interpret what is observed.
The systematic scientific process of: 1) experimental discovery, 2) dissemination via peer-reviewed publication, and 3) replication, is meant to protect against bias, falsehoods, or fabricated evidence which can have powerful negative consequences and often longstanding effects. Unfortunately, the way modern scientific research is funded can sometimes create incentives which motivate aspiring researchers to cheat in order to publish, support their findings, or to attract major funding.
Over the past six months, a shocking story of deception has emerged from the massive field of NIH-funded Alzheimer’s research, and the downstream market for drugs or other therapies to treat this debilitating disease—which have so far proven to be largely ineffective in clinical trials after many years of hype and hope.
For any family who lost loved ones or whose lives have been touched by the impacts of dementia, memory loss, and cognitive decline that are the hallmarks of those suffering from Alzheimer’s, the idea that their pain might have been avoided except for a researcher who lied, cheated, or faked results to get ahead is unthinkable.
However, based on a recent investigation conducted by the esteemed publication, Science, using insight from an independent image analyst and top Alzheimer’s researchers, fraud may be exactly what has shaped the ways doctors and researchers have tried to research treatments for the disease over the past two decades.
The story begins about a year ago when a junior neuroscientist and physician, Matthew Schrag, was asked to investigate claims being used to push an experimental Alzheimer’s drug into clinical trials. This case, while remarkable in its own potential for fraudulent misconduct, was only the tip of the iceberg and led to the analysis of one of the seminal papers used to support the leading theory of what causes damage in the brains of patients, or the beta-amyloid (Aβ) protein hypothesis of Alzheimer’s disease.
The paper, published in 2006, lists Sylvain Lesné as the first author. Schrag’s scrutiny of the paper revealed evidence that hundreds of images may have been doctored, including at least 70 images published in papers listing Lesné as an author.
Lesné’s landmark 2006 paper has been cited by close to 2,300 additional journal articles. It served as a major underpinning of the Aβ protein hypothesis and is one of the most-referenced studies on Alzheimer’s basic science. After its publication, annual NIH support for related research grew from zero at that time to $281 million in 2021, representing a cumulative total of more than $1.6 billion this fiscal year, or almost half the Alzheimer’s research currently being funded by the agency.
If reproducibility is the foundation of good science, journal editors and (peer) reviewers are the gatekeepers—a role which comes with significant responsibility to ensure that due diligence and rigorous skepticism are applied at key points in the publishing process and afterward.
Indeed, with the benefit of hindsight, there were indications that the emergence of the amyloid protein hypothesis and the work done by Lesné could have been flawed. Other leading researchers were not able to replicate key findings, including identifying or isolating a key form of the amyloid proteins or problematic oligomers (known as Aβ*56) that were suspected to result in problems in the brains of patients. Unfortunately, journals are reluctant to publish negative results or replicated research findings. This limits the ability to apply skepticism or doubt, in particular when theories are compelling (or have the power to create hope).
This scandal is a good example of how bad science hurts all scientific endeavors, and how those who cheat to get ahead in the field of medical research have poisoned the well and diminished public trust overall in doctors, scientists, and researchers.
A healthy dose of skepticism by peers could have prevented the fraudulent research from being published and possibly limited the amount of funding, time, and effort that has gone to waste trying to solve the mystery of Alzheimer’s pathogenesis over the past 16 years. To date, close to 100 of the 130 Alzheimer’s drugs that are working their way through clinical trials are based on targeting the amyloid plaques featured in the seminal paper authored by Lesné. This could possibly explain why these treatments have failed to live up to their promise.
As Matthew Schrag himself has stated, “you can’t cheat to cure a disease. Biology doesn’t care.”
Unfortunately, the scandal has been discovered too recently to prevent further funding for research being led by Sylvain Lesné, as he was recently awarded a coveted RO1 grant from the NIH, with up to five years of financial support. The project officer assigned to the grant is a program director at the NIH National Institute of Aging. This director was also a co-author with Lesné on the 2006 publication, raising additional questions, or at the very least creating poor optics.
What is done going forward, after all the investigations have been completed, will be critical to increasing or decreasing public faith in science. It may also open up new pathways for Alzheimer’s research, allowing those who have been exploring other theories to successfully compete for federal funding.