What’s Gone Wrong in Alzheimer’s Disease Research?
Published research once again found to contain fudged images—can any neuroscience research be trusted?
On July 19, 2023, Alzheimer’s disease research fraud claimed another victim. Stanford University president Marc Tessier-Lavigne resigned in the wake of the identification of improperly altered images in several published papers on which he was a senior author. Although Stanford University’s independent report fell short of finding him guilty of scientific misconduct, it pointed out that an important study overseen by neuroscientist Tessier-Lavigne in 2009 had “multiple problems” and “fell below customary standards of scientific rigor and process.” As a result of the months-long investigation, Tessier-Lavigne announced he will retract a 1999 Cell paper as well as two 2001 Science publications. “Two other papers, published in Nature, including the 2009 Alzheimer’s study, would also undergo what was described as comprehensive correction,” the New York Times reported. (1)
The student-run Stanford Daily first revealed the claims of misconduct on November 28, 2022. Reporter Theo Baker reached out to Elisabeth Bik, a biologist and science misconduct investigator, who responded to the Stanford Daily by email on November 28. (2)
“ ‘I hope that Dr. Tessier-Lavigne will not brush off these concerns as irrelevant. There appear to be a lot of visible errors in these papers, and some duplications are suggestive [of] an intention to mislead,’ she [Bik] wrote to the Stanford Daily. ‘Dismissing these as not affecting the data is not very reassuring. The reader might wonder how many non-visible errors might be present in other parts of the data’.” (2)
The website STAT News tackled the flawed Alzheimer’s research story November 30, 2022. Olivia Goldhill and Megan Molteni reported that “New findings of altered images in research co-authored by Stanford University president Marc Tessier-Lavigne add to the weight of allegations against him, according to experts on research misconduct.” (3)
Stanford University announced the investigation after being alerted to possibly altered images appearing in Tessier-Lavigne’s published work in four papers over seven years. (3)
“A subsequent analysis by Elisabeth Bik, a scientific integrity expert who specializes in identifying manipulated images, found an additional image that raises concern in a paper published in the journal Cell in 1999, two years earlier than the set of papers originally flagged to Stanford,” Goldhill and Molteni reported. Tessier-Lavigne was senior author on the 1999 Cell paper. (3)
“ ‘I would testify in court that’s been digitally altered,’ ” she [Bik] told STAT. ‘This actually changes everything. … It’s a more severe level of digital altering’.” (3)
The altered image in the Cell paper is a Western blot, which shows the presence of proteins. The authors’ claim was that the image showed a particular complex created by two proteins but only in the presence of a signaling molecule, a phenomenon that had not previously been reported. The authors’ claim was that this protein complex determined the directions in which axons—the long tail of the neurons—would grow.
Bik told STAT that, instead of just improving the appearance of the Western blot image, the alteration in the Cell paper “appears to be changing the actual results” of the Western blot test. (3)
The level of detail in the alteration also appeared to be intentional,
she added. Some image manipulations in other Tessier-Lavigne papers
are duplications, meaning the same Western blot is used to represent
different results, and researchers could conceivably use the same image
twice by mistake. “If they had reused the same blot, you could argue
negative blots all look the same, we just grabbed the wrong blot,” said Bik.
“In this figure, though, parts of a single western blot have been copied and
appear multiple times.” ... There are several other instances of apparent
alteration in the Cell paper, which have previously been flagged on PubPeer,
a site where researchers can discuss potential issues in papers but are far
more minor. (3)
According to STAT, the Cell paper has been cited by other researchers more than 850 times. (3)
The other four papers with altered images—two two Science magazine papers published in 2001 plus Nature papers in 2003 and 2009—reported studies performed in collaboration with several different university and biotechnology teams. Yet, as Bik told STAT in November 2022, “These problems seem to be following him along his career.” (3)
On July 19, 2023, a STAT headline announced: “Stanford president to resign after investigation finds he failed to ‘decisively and forthrightly’ correct research.” (4)
Jonathan Wosen reported that, “In an abrupt turn, Stanford president and renowned neuroscientist Marc Tessier-Lavigne announced Wednesday that he will step down as the university’s leader.” This new development followed “allegations of altered images in four papers co-authored by Tessier-Lavigne over a seven-year period” that had triggered Stanford University to investigate possible research misconduct. The report’s findings were made public on July 19, 2023. (4)
The report also probed the science surrounding the 2009 Nature paper
published during Tessier-Lavigne’s time at Genentech. This study,
which raised hopes for a new way to understand and potentially treat
Alzheimer’s disease, proposed a model in which two proteins, death
receptor 6 and amyloid precursor protein (DR6 and APP), interact in
a way that leads to neurodegeneration, a key feature of the devastating
disease. (4)
“The panel also found fault with Tessier-Lavigne’s response to concerns other scientists raised about several of the papers,” STAT’s reporting continued.
“ ‘If Principal Investigators fail to demonstrate an appropriate appetite for correcting instances of error, mistake, or misconduct, then the often-claimed self-correcting nature of the scientific process will not occur,’ the panelists wrote.” (4)
The panel concluded, however, that Tessier-Lavigne “did not personally engage in scientific misconduct.”
“The panel found numerous issues, however, with five studies in which Tessier-Lavigne was a major contributor, including evidence of data manipulation in scientific images,” Wosen reported. (4)
Tessier-Lavigne will step down as Stanford University President on August 31, but will remain a faculty member.
STAT’s Wosen consulted Dr. Matthew Schrag, an Alzheimer’s disease researcher at Vanderbilt University who has identified scientific misconduct in papers published by other high-profile Alzheimer’s disease researchers.
Schrag examined photographs of Western blots in an influential 2006 Nature article on Alzheimer’s disease and concluded that they had been manipulated, raising the question of possible fabrication. (4)
That 2006 paper by University of Minnesota’s Sylvaine Lesné and Karen H. Ashe’s team asserted that they’d discovered a new variant of the protein thought to be involved in Alzheimer’s disease memory loss, named “amyloid-β” [pronounced “amyloid-beta”]. Lesné and Ashe claimed they’d removed the new variant of amyloid-β from old mice with memory problems and injected it into young rats, which then also developed memory problems. Therefore, Lesné and Ashe asserted, the new protein alone “impairs memory independently of plaques or neuronal loss.” They named the new protein Aβ*56, pronounced “amyloid-beta star 56." (5)
Schrag examined the Western blots purporting to measure the amounts of Aβ proteins in the Lesné et al.paper. He found that a number of blots had been manipulated by cutting-and-pasting from another Western blot, for example; others had been improperly duplicated, in whole or in part, as an article in Science magazine reported. “Such manipulations can falsely suggest a protein is present—or alter the levels at which a detected protein is apparently found.” (6)
Following Tessier-Lavigne’s announcement he would resign as Stanford University President, Schrag told STAT, “In science at large and certainly in neuroscience, we’re seeing more episodes of data manipulation than any of us should feel comfortable with. It’s something that many of us are not comfortable talking about openly. And I think that we need to have this conversation,” emphasizing that he spoke for himself, not for Vanderbilt University. (4)
These published papers containing improperly altered or outright fabricated images have brought fame and fortune to the senior members of the teams that published them. Tessier-Lavigne’s papers containing improperly altered images have resulted in several prestigious awards as well as induction into the National Academy of Medicine. (3)
Lesné and Ashe’s influential 2006 Nature paper been cited by other researchers almost 2300 times, and it propelled the two senior authors, Sylvaine Lesné and Karen H. Ashe, into the forefront of Alzheimer’s disease research. (5)
Why should we be concerned about somewhat esoteric fabrications in research produced by prestigious laboratories that describe extremely esoteric experiments in neuroscience?
There’s currently an urgency in the field of neuroscience to find an effective treatment for Alzheimer’s disease; numerous treatments have already failed or actually made the patients worse. As the population ages, it’s projected that rates of Alzheimer’s disease could skyrocket. And anyone who’s had a friend or family member succumb to the soul-destroying illness understands the desperation that grips families, friends, and caregivers of Alzheimer’s patients.
The papers cited here as having improperly altered images from prestigious institutions don’t just lie quietly in the library waiting for someone to find out they’re fraudulent—they’re spreading from laptop to laptop, influencing the direction of Alzheimer’s research into causality, into treatments, into the possibility of a cure.
How many billions of dollars have been wasted searching for Alzheimer’s disease treatments based on not just faulty, but falsified, research? The ineffectual search for an Alzheimer’s disease treatment mirrors, in many ways, the search for an AIDS vaccine or a truly effective, non-toxic antiviral drug that people with AIDS as well as healthy people trying to avoid AIDS don’t have to take for life. Are all of these endeavors failing because they’re targeting an incorrectly identified cause of these illnesses? Or are they failing because honest scientists are trying to reproduce experiments they don’t realize are fraudulent and have no hope of successfully replicating? (7)
Science is clearly doing a very poor job of policing itself.
BIBLIOGRAPHY
1. Stephanie Saul; “Stanford President Will Resign After Report Found Flaws in His Research”; New York Times, July 19, 2023.
2. Theo Baker; “Stanford president’s research under investigation for scientific misconduct, University admits ‘mistakes’ “; Stanford Daily, November 28, 2022.
3. Olivia Goldhill and Megan Molteni; “ ‘This actually changes everything’: Altered image in 1999 paper raises potential peril for Stanford president”; STAT, November 30, 2022.
4. Jonathan Wosen; “Stanford president to resign after investigation finds he failed to ‘decisively and forthrightly’ correct research”; STAT, July 19, 2023.
5. Lesné, S., Koh, M., Kotilinek, L. et al. “A Specific Amyloid-β Protein Assembly in the Brain Impairs Memory.” Nature 440: 352–357 (2006). https://www.nature.com/articles/nature04533
6. Charles Piller; “Blots on a Field?” Science News, July 21, 2022. Also: Science, Vol 377, Issue 6604.
7. Neenyah Ostrom; “Alzheimer’s + Long Covid & ME/CFS ‘Brain Fog’: What Do They Have in Common? The diagnostic protein ‘blobs’ of Alzheimer’s disease may not be its cause after all—and some sleuthing suggests it may all be fraud.” January 26, 2023. SubStack: https://immuneillnessreport.substack.com/p/alzheimers-long-covid-and-mecfs-brain
ABOUT THE AUTHOR
Neenyah Ostrom was the first reporter in the United States to report weekly for a decade on ME/CFS. Her reporting on the Chronic Fatigue Syndrome epidemic from 1988-1997 is getting increased attention thanks to Robert F. Kennedy Jr. He discusses her work extensively in his 2022 best seller, The Real Anthony Fauci. Ostrom’s groundbreaking reporting on Chronic Fatigue Syndrome and AIDS appeared in the New York Native from 1988 to 1997.
Ostrom wrote the Foreword to the recently published THE REAL AIDS EPIDEMIC: How the Tragic HIV Mistake Threatens Us All by Rebecca Culshaw, Ph.D.
Ostrom is the author of four books about the Chronic Fatigue Syndrome epidemic: What Really Killed Gilda Radner? Frontline Reports On The Chronic Fatigue Syndrome Epidemic (1991; TNM Inc., New York, NY), 50 Things Everyone Should Know About The Chronic Fatigue Syndrome Epidemic And Its Link To AIDS (1992; TNM Inc. and St. Martin’s Press, New York, NY; published in Japanese by Shindan-to-Chiryo, 1993; and in French by Les Editions Logiques, 1994), and America’s Biggest Cover-Up: 50 More Things Everyone Should Know About The Chronic Fatigue Syndrome Epidemic And Its Link To AIDS (1993; TNM Inc., New York, NY); and America’s Biggest Cover-Up: 50 More Things Everyone Should Know About The Chronic Fatigue Syndrome Epidemic And Its Link To AIDS, Updated 2nd Edition (2022, available as a Kindle ebook and paperback on Amazon.com). Her most recent book, Ampligen: The Battle for a Promising ME/CFS Drug (2022) is available as a Kindle ebook and paperback on Amazon.com
In 1995, Ostrom and New York Native were recognized as having reported one of the top 25 most-censored stories in the U.S. press by 1995’s Censored: The News That Didn’t Make The News And Why (The 1995 Project Censored Yearbook by Sonoma State University Professor Carl Jensen, introduction by Michael Crichton; published by Four Walls Eight Windows, New York, NY, 1995).
Ostrom is ghostwriter/editor of seven popular science books. Additionally, she was an editor of Total Breast Health: The Power Food Solution For Health And Wellness by Robin Keuneke, which was chosen as a Publishers Weekly “Best Book of 1998” in the category of Breast Health (Kensington Publishing Corp., April 1998).