A NEWS ARTICLE RECENTLY HIGHLIGHTED AN INFLUENTIAL and frequently-cited publication in Alzheimer’s disease research that might be based on fraud. While I encourage you to read the extraordinary detective work by Science author Charles Piller, I want to present some of the stories here and discuss their implications. Has he uncovered a case of Alzheimer’s research fraud?
The work in question is a pillar underlying much of the current research approach to the form of dementia known as Alzheimer’s disease. Here is how the recent sleuthing began, according to Piller:
“In August 2021, Matthew Schrag, M.D., Ph.D., a Vanderbilt University (USA) neuroscientist and physician, got a call to plunge him into a maelstrom of possible scientific misconduct. A colleague wanted to connect him with an attorney investigating an experimental drug for Alzheimer’s disease called Simufilam.
The drug’s developer, Cassava Sciences, claimed it improved cognition, partly by repairing a protein that can block sticky brain deposits of the protein amyloid beta (Aβ), a hallmark of Alzheimer’s.
The attorney’s clients — two prominent neuroscientists who are also short sellers who profit if the company’s stock falls — believed some research related to Simufilam may have been “fraudulent,” according to a petition later filed on their behalf with the U.S. Food and Drug Administration (FDA).”
The original Alzheimer’s disease study
In their heralded 2006 research paper, published in Nature, University of Minnesota (USA) scientist Sylvain Lesné and colleagues presented a central link in the “amyloid hypothesis” of Alzheimer’s disease (A.D.) — the belief that the cognitive problems associated with A.D. are mostly the product of amyloid beta (Aꞵ) proteins, also known as plaques.
The study authors reported the discovery of a previously unknown subtype of Aꞵ called Aꞵ*56, which they then showed caused memory impairment when injected into young rats.
While researchers had recognized Aꞵ plaques as a common characteristic of Alzheimer’s disease as far back as 1906, Lesné’s work suggested that these proteins caused memory and cognitive declines. The prevailing view of amyloid plaques as central to Alzheimer’s disease had some new potent evidence.
The 2006 publication contributed to the United States government directing most of its funding to Aꞵ’s role in A.D. pathogenesis. Aging expert Dr. Peter Attia explains:
“This research provided the foundation for subsequent development and approval of anti-amyloid medications (e.g., aducanumab) for Alzheimer’s disease treatment. The logic is simple: Aꞵ plaques cause the disease, so removing them should slow stop disease progression.”
Unfortunately, in practice, the hypothesis seemed off. Almost all experiments using drugs targeting the amyloid plaques have failed to have a positive effect on cognition. Even before the challenges to Lesné’s work, researchers had some skepticism about amyloid plaque as a causative agent of Alzheimer’s disease. It hasn’t helped that autopsies show many elderly individuals with normal cognition have significant amounts of amyloid plaque.
This NBC News headline illustrates this growing skepticism: “As new Alzheimer’s drugs have failed, scientists are shifting focus to other potential causes.”
The amyloid hypothesis has “been taking a lot of hits lately,” according to Donna Wilcock, Ph.D., the Assistant Dean for Biomedicine at the University of Kentucky (USA). “The drug trials keep coming through and for the most part, failing.”
Enter neuroscientist Matthew Schrag
The phone rings. It is August 2021, and Dr. Matthew Schrag receives a call that will propel him into scientific controversy. A colleague desired to connect the American neuroscientist and physician with a lawyer investigating an experimental drug for Alzheimer’s disease, Simufilam.
Cassava Sciences claimed the drug improves cognition, partly through the repair of protein amyloid beta (Aβ), a hallmark of Alzheimer’s disease.
The lawyer’s clients — two well-known neuroscientists who are also short sellers who profit if the company’s stock falls — believed some research related to Simufilam may have been “fraudulent.” The clients offered these claims in a petition filed on their behalf with the United States Food and Drug Administration (FDA).
Alzheimer’s dementia research fraud?
The plot thickens as Schrag applies his expertise to examine published images about the drug and its underlying science. He finds altered or duplicated images in dozens of journal articles. The protagonist of our tale, Dr. Cassava, denied any misconduct.
The most influential Cassava-related paper appeared in 2012. The authors reported an association between insulin resistance, the formation of amyloid plaques, and Alzheimer’s disease. The researchers examined dead brain tissue, frozen for a decade and then partially thawed and cut.
Schrag offers that this method of looking for brain signals contradicts basic neurobiology. Moreover, Schrag and others say it contradicts basic neurobiology. In addition, there is no evidence that other investigators have replicated the results.
The neuroscientist does not go as far as calling the research fraud; rather labels his concerns as red flags. Schrag would need access to original, unpublished images and some raw numerical data.
Amyloid and Alzheimer’s disease — My take
“You can’t cheat to cure a disease. Biology doesn’t care.” — Dr. Matthew Schrag.
Is it possible that the seminal 1996 research publication haAlzheimer’shers planning experiments based on an erroneous premise? Or that valuable researcher’s time and funds have been better used elsewhere? If the allegations are true, that is the real tragedy.
Fortunately, science has a way of correcting itself. I don’t know if the allegations are true, but if other researchers cannot replicate the findings, we will move on in another direction.
Dr. Peter Attia notes that the rising burden of Alzheimer’s dementia in the United States has motivated Congress to more than quintuple the National Institutes of Health (NIH) budget for Alzheimer’s dementia-related research. Some of the allocated funds will be aimed at novel hypotheses on Alzheimer’s disease causes.
Thank you for joining me today in this look at a potential case of Alzheimer’s disease research fraud.
The information I provided in this blog is for educational purposes only and does not substitute for professional medical advice. Please consult a medical professional or healthcare provider if you seek medical advice, diagnoses, or treatment. I am not liable for risks or issues associated with using or acting upon the information in this blog.
