Key elements of influential Alzheimer’s study may have been fabricated, report says

Henry Magendantz, a participant in the Aduhelm clinical trial, finishes receiving an infusion of the drug at Butler Hospital in Providence, R.I., May 27, 2021.KAYANA SZYMCZAK/NYT

Alzheimer’s disease has long been a formidable foe for drug makers despite billions of dollars poured into federal research.

Nearly two decades passed before the government approved a new Alzheimer’s medicine in June 2021, from Cambridge’s Biogen. In April, Medicare dealt a major blow to that drug, Aduhelm, refusing to cover it for most patients because of continuing doubts about whether it is effective against the disease, which is the most common form of dementia.

Now the field of Alzheimer’s research has received another black eye. An investigative report in the journal Science said that an influential paper published in Nature in 2006 allegedly contained fabricated data and that it fueled a popular but unproven theory into the causes of the disease.

What did the Science article say?

It reported that key elements of the Nature paper, whose lead author was Sylvain Lesné, a neuroscientist at the University of Minnesota medical school, contained manipulated data images. He is under investigation by the university and did not respond to requests from Science for comment.

Why was the Nature study significant?

It looked at cognitive decline in mice and theorized that a specific amyloid beta protein, called Aβ*56, may be responsible for the disease. Matthew Schrag, a neuroscientist and physician at Vanderbilt University, analyzed images from the 2006 paper and found signs that results from experiments may have been fabricated, according to the Science article published last week. Schrag avoided using the word “fraud” in his critique. “I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he said in Science.

What does amyloid have to do with Alzheimer’s disease?

For years, researchers have known that the sticky protein often clumps into plaques in the brains of people with the disease. Scientists, however, continue to debate whether amyloid causes Alzheimer’s or is merely a byproduct of the illness. Aduhelm, Biogen’s monoclonal antibody approved by the Food and Drug Administration last year, targeted amyloid but a different form of the protein than the one Lesné homed in on. There are dozens of different forms, scientists say.

If the Nature paper contained fabricated data, does that demolish the amyloid hypothesis?

Not necessarily, according to some scientists. “This was kind of a mainstream hypothesis and still is, and wasn’t based on any one publication, although admittedly [the 2006 paper] was high profile,” said Charles Glabe, a professor of molecular biology and biochemisty at the University of California Irvine. Glabe was listed as a coauthor on Lesné’s paper because his laboratory provided one of the antibodies used in the research “It’s never good to have a fabrication in science,” he added. “It gives everybody a black eye, and sadly it happens more often than we think.”

Dennis Selkoe, co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, posted on the website Alzforurm.org that “it is not a scientific setback at all” because many other papers have suggested amyloid proteins may cause Alzheimer’s disease. “Rare examples of malfeasance and fraud occur in all fields of human endeavor, and I do not feel Sylvain Lesné’s acts are a reflection of AD research over the last four decades,” Selkoe told The Boston Globe in an e-mail.

Rudolph Tanzi, vice chairman of the neurology department at Massachusetts General Hospital, said he still believes targeting amyloid plaques is one of the best hopes for Alzheimer’s patients. The 2006 paper, he said in an e-mail, “actually had very little influence on the amyloid hypothesis or the direction of Alzheimer’s research” because within two years, scientists had been unable to replicate the results.

But other scientists have long felt researchers have focused too much on amyloid and said the Science investigation only bolsters their view.

“For many of us, this is not surprising,” Brian Silver, interim chair of the department of neurology at UMass Memorial Health, said in an e-mail. “The amyloid hypothesis has been challenged for at least a decade. While having amyloid accumulation may be necessary for the disease to occur, it is alone not sufficient. Autopsy studies show patients with significant accumulation of amyloid and no evidence of dementia during life. The current thinking is that another protein (tau) may actually be the driver of the disease progression.”

What might doom the amyloid hypothesis?

Biogen, Roche, and Eli Lilly and Company are all testing three other experimental drugs that target amyloid in late-stage clinical trials, and results are expected in the coming months. If all those drugs fail, Selkoe said in Science, the hypothesis “is very much under duress.”

What does Biogen make of the Science article?

A spokeswoman for the company said Biogen had no comment. Dominic Walsh, head of the Alzheimer’s Disease and Dementia Research Unit at Biogen, said on Alzforum.org the allegations are “disturbing and sad” but have “little consequence for the amyloid hypothesis.” The upcoming trial results, he wrote, will deliver the most important verdict.