The most seminal paper in Alzheimer's pathology has been retracted due to allegations of fraud

Leading many to question the state of Alzheimer's research as a whole.

Over the past three years I have brought attention towards Alzheimer’s research and controversies surrounding the field, first starting with questions regarding the fast-tracked approval of the immunotherapy Aducanumab (Aduhelm) which led to several FDA committee members leaving their position.

Following this highly controversial approval additional immunotherapies were also seeking approval. However, at the same time these rushed approvals were occurring a new scandal hit the field of Alzheimer’s research in 2022, in which it was alleged that one of the most critical papers in elucidating Alzheimer’s pathology came under fire for manipulated figures.

In short, in the decades prior may scientists and clinicians began to recognize the presence of amyloid plaques in those who were recognized to have signs of neurocognitive degeneration. However, researchers were never able to tie a clear relationship between the two i.e. no researchers were able to find evidence that the amyloid plaques were the reason for Alzheimer’s Dementia.

It wasn’t until the 2006 paper from Lesné, et al. that researchers were (allegedly) finally able to tie the presence of amyloid to memory impairment. Specifically, from this study it was suggested that a specific amyloid subtype named Aβ*56 was associated with memory deficits in older mice, and when administered to young mice the young mice also exhibited memory deficits.

Of course, such a discovery would be groundbreaking as it would tie amyloid presence with the pathology associated with Alzheimer’s Dementia, leading to the predominant focus of Alzheimer’s research being around the amyloid hypothesis. In the following years research endeavors were focused almost solely on treating and managing amyloid, and at the time of this writing the paper from Lesné, et al. has been cited by more than 1,000 papers according to a PubMed search, although it appears that this paper is likely to have been cited by nearly 2,500 papers.

Remember that one of my main gripes with research is the idea that one must tie the presence of some biomarker or metabolite to the pathology of a disease- if detected, then pathologize. Just because one finds amyloid within the brains of those with severe neurocognitive impairments does not necessarily mean that the amyloid was the cause of the impairments. And indeed, several bits of research have come out recognizing that many otherwise healthy individuals with no signs of cognitive impairments also appear to have amyloid formation within their brains.

In short, the picture around Alzheimer’s Dementia is far more complex than is being proposed by amyloid hypothesis enthusiasts, and yet billions of dollars is being put directly towards anything that aligns with the amyloid hypothesis. In fact, dissenting viewpoints are unlikely to receive funding or the same amount of attention.

But this all came to a head in 2022 when Science published an investigatory article in which a researcher-turned-sleuth recognized that some of the figures provided in the Lesné, et al. paper appeared to have been duplicated, suggesting data manipulation:

By all accounts this should be considered one of the biggest scandals in research. Imagine billions of dollars, thousands of published papers, and millions of people affected by dementia being lied to regarding the actually cause of Alzheimer’s Dementia.

And yet while this upheaval in Alzheimer’s research was brought into the light of public scrutiny, the FDA continued to approve several new immunotherapies targeting the exact thing that is now being questioned, including another Biogen-related immunotherapy called Lecanemab (Leqembi) receiving accelerated approval:

And more recently Lilly received FDA approval for their anti-amyloid immunotherapy Donanemab (Kisunla™):

Strange that no hesitation was made in such approvals especially with such a controversy hanging over the entire field of Alzheimer’s research.

However, after nearly two years of controversy the Lesné, et al. paper was finally retracted in late June 2024:

Nearly all of the included authors agreed with retraction of the article- everyone except for the first author Lesné, of course. One other author, Austin Yang, did not provide comment regarding the retraction.

The Nature retraction makes the following comment:

The authors wish to retract this article. Concerns have been raised regarding figures in this article, including Fig. 2c and Supplementary Fig. 4, which show signs of excessive manipulation, including splicing, duplication and the use of an eraser tool. The data cannot be verified from the records. We consider that the appropriate course of action is to retract the article.

Ming Teng Koh, Linda Kotilinek, Rakez Kayed, Charles G. Glabe, Michela Gallagher and Karen H. Ashe agree with the retraction. Sylvain Lesné disagrees with the retraction. Austin Yang has not responded to correspondence from the Editors about this retraction.

Readers may be interested in a Science article from early June 2024 which discussed the retraction. It’s here where the “nearly 2,500” citations comes from, and at the time this paper would have been the most-cited paper to ever be retracted, only to be immediately beat out by another retraction in the following days.

Probably one excerpt that provides a good deal of context is the following, which points to the fact that research regarding the specific amyloid subtype discovered by Lesné, et al. didn’t prove fruitful in clinical research. More importantly, the retraction has resulted in scientists questioning if such an amyloid subtype even exists:

The 2006 paper suggested an amyloid beta (Aβ) protein called Aβ*56 could cause Alzheimer’s. Aβ proteins have long been linked to the disease. The authors reported that Aβ*56 was present in mice genetically engineered to develop an Alzheimer’s-like condition, and that it built up in step with their cognitive decline. The team also reported memory deficits in rats injected with Aβ*56.

For years researchers had tried to improve Alzheimer’s outcomes by stripping amyloid proteins from the brain, but the experimental drugs all failed. Aβ*56 seemed to offer a more specific and promising therapeutic target, and many embraced the finding. Funding for related work rose sharply.

But the Science investigation revealed evidence that the Nature paper and numerous others co-authored by Lesné, some listing Ashe as senior author, appeared to use manipulated data. After the story was published, leading scientists who had cited the paper to support their own experiments questioned whether Aβ*56 could be reliably detected and purified as described by Lesné and Ashe—or even existed. Some said the problems in that paper and others supported fresh doubts about the dominant hypothesis that amyloid drives Alzheimer’s. Others maintained that the hypothesis remains viable.

That debate has continued amid the approval of the antiamyloid drug Leqembi, which modestly slows cognitive decline but carries risks of serious or even fatal brain swelling or bleeding.

Alzheimer’s research is not in a good spot

Unfortunately, this retraction scandal isn’t the only scandal to hit Alzheimer’s research within the past few weeks.

Just recently a medical professor at the City University of New York named Hoau-Yan Wang was indicted on charges of fraud related to allegedly manipulated images and data that he used to secure research grants from the NIH to the tune of nearly $16 million. In this case, the grant money was related to research into an investigatory Alzheimer’s drug called Simufilam which was being developed through a partnership with the company Cassava Sciences. The funding was provided for early clinical trial research regarding Simufilam, however the prospective therapeutic is now within late-stage clinical trial research.

A summary from NBC News provides the following account of the fraud:

The charges in the indictment are related to the alleged fabrication of research images and data that Wang may have used to secure federal grants from the National Institutes of Health.

Wang, a medical professor at the City University of New York, collaborated with Cassava Sciences, a pharmaceutical company based in Austin, Texas, as it investigated an Alzheimer’s drug candidate called simufilam. He was awarded some $16 million in grants for early-stage drug development in collaboration with Cassava, according to the indictment.

The indictment charges Wang with one count of fraud against the United States, two counts of wire fraud and one count of false statements. It accuses Wang of manipulating or adding to images of Western blots, a laboratory method that researchers use to identify proteins, in order to bolster evidence and help secure grants.

The indictment also suggests that Wang may have lied to scientific journals to substantiate his research, which contributed to the early development of simufilam.

The drug is currently in a late-stage clinical trial, and some 735 patients had participated as of May 2024, according to a news release from Cassava last month.

If the name “Simufilam” sounds familiar, it was the drug which sparked the dive into the rabbit hole that resulted in the Lesné, et al. image manipulation coming to light. In that regard there’s a bit of irony in Wang being indicted for fraud right on the heels of the Lesné, et al. paper being retracted.

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The ongoing Alzheimer’s debacle is a clear window into the questionable nature of science research and funding. Most of this research is being funded by tax payers who may be none the wiser to the malfeasance that is going on behind the scenes, but who nonetheless will spur on such research endeavors over the hope that some effective treatment may become available.

At the same time, regulatory agencies put in charge of ensuring aboveboard drug approvals may be just as complacent in wrongdoing, and may in fact share close ties with those in the pharmaceutical industry, as was alluded to after an investigation by Congress in late 2022 which noted that the FDA’s approval of Aduhelm did not follow typical regulatory approval processes:

There’s an all-around high degree of misconduct taking place; most of which are going unscrutinized and unreported. It’s quite shocking how little attention is being provided towards all of the alleged fraud that is being conducted- and we wonder why the public is remains ignorant of the type of bad science that goes on in the background.

Although Alzheimer’s research is under fire right now, it’s important to remember that this is representative of research as a whole and the high degree of fraud, misconduct, and lack of integrity that is likely taking place.

There’s a lot of bad science going on, and we need far more people to recognize and call out the bad science when possible.

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