Jul 25 2022

The Alzheimer’s Research Fraud Case

We are still relatively early in the investigation of possible fraud or misconduct relating specifically to amyloid beta (Aβ) in Alzheimer’s disease, so consider this all preliminary. However, independent analysis does allegedly find some highly suspect data in a series of images used in publications by one particular researcher, Sylvain Lesné of the University of Minnesota.  Science magazine has done a good review of what we know at this time. I will quickly review the status of this investigation and what the whole episode means for scientific research in general, and Alzheimer’s research in particular.

For background, Alzheimer’s disease (AD) is a complex neurodegenerative disease and the major cause of dementia, a chronic loss of global cognitive function, especially memory. AD has been extremely frustrating from a scientific and medical point of view. While there is a great deal of research and it has made impressive progress in understanding the pathophysiology of the disease, we remain without a single coherent “smoking gun” cause of the disease. The problem is (as with other neurodegenerative diseases) that there is a lot happening when brain cells age and die. The trick has been to not only identify markers of AD in the brain, but to understand what role those markers play in the disease. Specifically, are they driving the disease, or are they just a consequence of it?

In medicine there are two main ways to test a causal hypothesis for a correlational marker – can we transfer the disease by transferring the marker, and can we cure the disease by treating the marker? That last question is the ultimate goal of medical research, to find a cure, or at least a disease-modifying treatment. If we can prevent, slow down, stop the progression, or even reverse AD by interfering with one aspect of the disease, then that aspect is likely what’s driving it. But also – we have effective treatments, and everyone is happy.

This is where AD research gets very frustrating. Despite having many pathological clues to follow, researchers have been unable to close the loop – to find a disease-modifying treatment based on our basic science knowledge of AD. This leads to a lot of head-scratching and debate – is AD caused many by the build up of toxic proteins, by impaired neuronal function, by inflammation, or something else? One of the prominent theories of AD is that a major contributor to the disease is a build up of toxic protein, specifically amyloid beta (Aβ). But the Aβ theory has not led to a cure, which has led to many Aβ skeptics in the Alzheimer’s research community.

This is where we get to the current concerns about possible research misconduct. A 2006 paper by Lesné and others seems to show that a particular oligomer of Aβ, Aβ*56, impaired memory in mice, and that when the protein was transferred to healthy mice would cause significantly impaired memory. That is the first step in proving causation – transferring the marker transfers the disease. This paper was a huge boost to the Aβ hypothesis of AD and was significantly influential on later research. However, the results were hard to replicate, with only a few other labs publishing similar results. (When most or all of a scientific phenomenon comes out of one lab or from one researcher, that is a red flag.)

This paper did not end the debate so much as keep it going, breathing new life into the Aβ theory of AD, but certainly not eliminating its critics or those who support other theories of causation. The paper and subsequent work by  Lesné also inspired several pharmaceutical companies to try to develop treatments based on neutralizing Aβ*56. Most infamously was Aduhelm, which the FDA approved based entirely on reducing amyloid as a marker of AD without proving clinical efficacy. This decision was unprecedented and really stuck in the craw of Aβ critics.

With that as background, we now learn that another neuroscientist, Matthew Schrag, has found some concerning problems with Lesné’s Aβ*56 work. In reviewing images of Western Blots and other data on his papers he found concerning evidence for image duplication and cropping artifacts. Data manipulation of scientific images is an egregious example of misconduct, and if the suspicions are true would call into question the body of Lesné’s work. The Science article gives all the details, but the short version is that there is evidence of multiple manipulated images across many papers, and this evidence seems to follow Lesné (not any of his collaborators). Shrag also notes that Lesné’s was entirely in charge or producing the images for the concerning publications. This does not absolve his coauthors, however, if they signed off on fraudulent images without adequately checking the work. If these allegations are true it will also explain why the work has been so hard to replicate and why it still has not led to a proven treatment for AD.

There are lots of estimates for how much this fraud, if that is what it is, has caused society. In reality it’s hard to say. This is just one element of a complex scientific controversy. There are certainly supporters of the Aβ theory without Lesné’s Aβ*56 work, but his publications definitely had a profound effect on the field. It is likely that his studies have influenced hundreds of millions of dollars worth of later research, perhaps more. It’s honestly hard to say.

I do want to point out that the way this played out was fairly typical for scientific fraud. The initial findings were dramatic, but met with immediate skepticism, and were difficult to replicate. Many researchers had problems with Lesné’s work even prior to allegations of misconduct. One prior colleague even withdrew a paper they were working on together (when Lesné was a student) and cut professional ties with him, because of suspicious scientific behavior. Scientific fraud like this tends to work itself out, because you cannot fool nature. I suspect that many people who cheat on scientific papers (cut corners, engage in P-hacking, etc.) think they are just cleaning up the case for what is actually true. But this does not work in science. Confirmation bias is too easy – “cleaning up the data” is just another word for fraud.

But even though we tend to weed out scientific fraud in the end, it can cause massive waste and inefficiency in the meantime. Lesné may have distorted an entire (and difficult) field of research. If the ongoing investigations confirm Shrag’s case (which is already pretty compelling) then it will also tend to taint the Aβ theory of AD, but this would not be fair either. Aβ may still turn out to be important in the pathophysiology of AD, even if one researcher did engage in fraud to promote it.

Further, this case serves as another cautionary tale about how important it is in science to have multiple layers of verification. Journals in particular could be doing more to routinely screen data images submitted as part of papers for signs of manipulation. Filtering out fraud as early on in the process as possible is critical to preventing subsequent waste. For high stakes research, that waste can be in the hundreds of millions of dollars or more. In medical research this can also influence the lives of patients, their hopes and faith in the medical system.

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