Alzheimer’s theory under scrutiny amid fabrication claims

Despite manipulation of images, researchers say origins are sound

A year ago, Alzheimer’s researchers expressed guarded optimism. The first new drug in nearly two decades was about to hit the market, and pharmaceutical companies had potentially stronger drugs in the pipeline.

But the controversial drug Aduhelm barely has been prescribed amid Medicare payment restrictions. And researchers now face questions about whether they’ve wasted time and federal grant money on a dead end after Science magazine reported last month that an influential 2006 study relied on fabricated images to support its conclusion. The magazine said the study possibly misdirected Alzheimer’s research for the past 16 years.

Dr. Karen Ashe, a senior University of Minnesota scientist, acknowledged a junior colleague appears to have manipulated two images, but said those actions did not affect the study’s wording and conclusions.

And no less an authority than the British scientist who first proposed that Alzheimer’s is triggered by amyloid beta plaques in patients’ brains told USA TODAY that three decades of subsequent medical evidence still bolsters that theory. He conceded after years of amyloid-targeting drug failures Alzheimer’s might require a multi-drug approach to meaningfully slow the mind-robbing disease that afflicts 5.8 million Americans.

“I’m confident we will gradually push back on Alzheimer’s disease in the same way that we’ve pushed back on cancer and so on,” said Dr. John Hardy, a London geneticist. “It’ll be a slog . ... There’s going to be no sudden breakthrough.”

‘Didn’t look natural’

Doctors and scientists will have a new topic to discuss this week in San Diego at the Alzheimer’s Association International Conference, which showcases the latest in research in new drugs, diagnostic tools and caregiving advances.

The Science article raised questions about the study from over a decade and a half ago that claimed to discover a type of protein linked to Alzheimer’s disease.

The article centered on a Vanderbilt University neurologist’s investigation of images used in the 2006 research paper on the discovery of a type of protein called amyloid beta star 56. Dr. Matthew Schrag concluded published images used to support the research were likely altered, though he stopped short of calling the research fraud, noting he did not have access to the original unpublished images or underlying data. His research was performed outside his duties at Vanderbilt University Medical Center.

“They were things that you would expect to see with a typical photo editing software like Photoshop,” Schrag told USA TODAY. “They just didn’t look natural.”

The story quoted other experts who agreed the images appeared to be altered.

In an editor’s note, the scientific journal Nature that first published the 2006 study said it is investigating concerns and advises readers to use caution when interpreting results.

“Our responsibility is to the scientific record, not the implications of the retractions themselves,” the magazine said in an emailed statement. “We welcome outside scrutiny of the papers that we publish. Correcting the scientific record, whether issues result from honest errors or misconduct, is an important part of what we do, and we take the responsibility seriously.”

Sylvain Lesné, a University of Minnesota neuroscientist and first author of the 2006 paper, did not return an email message.

Ashe, the University of Minnesota professor of neurology who hired Lesné, said she initiated a retraction but has not been able to produce legitimate reasons to do so. Nature requires all eight co-authors to sign off on a retraction. So far, six of her co-authors have refused to do so.

“I’m not saying it’s okay to manipulate figures,” she said in an email. “But the figures in question were manipulated in a way that made them look nicer but did not affect one word in the paper. The upshot is, I would have to tell a lie to retract the paper.”

School officials said in a statement the university is aware of the questions about the images used in the study and “will follow its processes to review the questions any claims have raised.”

While the the Nature study has been widely cited by other scientists, Alzheimer’s experts have downplayed its role in discovering potential drugs.

Dr. Dennis Selkoe, a Harvard Medical School professor of neurology, said he was among the researchers who questioned the Nature study when it was first published and said it now appears to be a “very sad example of human fragility and malfeasance.” He said the apparent misconduct does not affect decades of research into the cause of Alzheimer’s disease.

Rudy Tanzi, an Alzheimer’s expert at Massachusetts General Hospital in Boston, agreed, saying the flawed study was “egregious” but “had virtually zero effect on progress” in the field.

Tanzi said the field paid no more attention to the study after about 2008, because no one had been able to replicate its findings and that the Science story went too far in suggesting that years of research may have been wasted. He called it “hyperbole” to say the paper had any impact on the amyloid hypothesis or the larger field.

Alzheimer’s researchers have long theorized the disease is triggered by amyloid beta that builds up and forms plaques in the brain of Alzheimer’s patients. The amyloid cascade hypothesis, described by Hardy and a co-author in papers in 1991 and 1992 following the discovery of a genetic mutation in families with an inherited form of the disease, has influenced research funding and clinical studies of potential drugs ever since.

“This unfortunate incident does not alter the overwhelming genetic, neuropathological, animal modeling and even human trial evidence that lowering amyloid of all forms ... can modify the disease,” Selkoe said in an email.

In a post to the research website Alzforum, Ashe said it was “devastating” to learn Lesné “may have misled me and the scientific community through the doctoring of images.”

Yet, she said it’s “simply untrue” to imply this misconduct claim led to years of drug development failures.

While Schrag’s investigation called into question Lesné’s imaging work for the paper that identified amyloid beta star 56, a subtype of amyloid beta called an “oligomer,” he said other studies support the idea that oligomers play a role in the disease.

No ‘magic bullet’

The National Institutes of Health has awarded hundreds of millions in grants to researchers studying amyloid as a potential culprit in Alzheimer’s, which is the most common form of dementia. Pharmaceutical companies also have had repeated failures when studying amyloid-targeting drugs.

The only amyloid-targeting drug the Food and Drug Administration has approved is Biogen’s Aduhelm for people with mild forms of the disease. The FDA’s outside expert advisers recommended against approval, which was based on two studies that were ended early and yielded mixed results. When the agency approved the drug anyway, three advisers quit in protest. Rather than pay for the drug for Alzheimer’s patients, the Centers for Medicare and Medicaid Services limited coverage to people enrolled in clinical trials.

Biogen has laid off staff and wrote off the value of its Aduhelm inventories through the end of June, the company said in a July 20 filing. Once a potential blockbuster, Aduhelm sales totaled just $2.9 million through the first six months of this year.

Biogen and Eisai expect to report results this year from a study of the drug lecanemab.