Thread by @KarlHerrup

Indulge me in a long thread with thoughts on the Piller bombshell in Science about the fraud surrounding the Lesné Aß*56 data.

Bottom line: The scale of the fraud is horrifying but the significance to the #Alzheimer’s field is seriously exaggerated.

First, the fraud illustrated by Piller is clear and deliberate. Big problem. Science is based on trust and doesn’t work if we can’t have full faith in published data. If you say this is a picture of X, it had better not be a Photoshop of two V’s with one inverted and flipped.

And let’s be clear that not all threats are as discoverable as Piller’s western blot example, e.g., someone publishes a picture of an Aß plaque in a human brain and says it was found in a mouse brain (sound familiar?) You don’t need to manipulate an image to lie.

We need to ferret out every single case of fraud. But I’ve got a few contrarian thoughts I’d like to share. Piller cites several experts who lament how this fraud led to lots of “wasted NIH funding and wasted thinking”. I think that’s a pretty serious overstatement.

First, Aß*56 may be a fantasy, but Aß*56 is not the whole story. The oligomer hypothesis rests on many eminent shoulders, with supporting data from many reputable labs. Lesné et al is much cited (as one of the firsts), but it’s not the only claim for the importance of oligomers.

Second, the many iterations and variants of the amyloid cascade hypothesis do not depend on the Lesné findings and Aß*56. I agree that NIH funding has been wasted by chasing the amyloid cascade, but the blame for that is not the result of the actions of a single charlatan.

Third, what a coincidence that just months before the announcements of the results of the next major anti-amyloid trials (with not much optimism for major successes), the field has found a convenient scapegoat.

Not our fault! Lesné fooled us!!

Sorry, not buying

Pardon my cynicism, but this sounds like a desperate search for an off-ramp from a looming embarrassment. There is no way an entire field and all its players – universities, PhRMA, NIH, NGOs – were seriously misled by just these fraudulent papers, despite their number.

I’d even go so far as to speculate that had none of Lesné’s work ever been published, our portfolio of clinical trials would not look appreciably different. The river of amyloid-is-AD thinking has many tributaries, not just one.

Do not misunderstand me. I soundly condemn this industrial grade fraud. A full investigation is needed and there must be consequences. I, as others, was personally skeptical of the Aß*56 idea, but personal skepticism is not enough. Protecting the literature is paramount.

We can’t undo all the damage but let’s use this as a teaching moment. Let’s use Piller, 2022 as a part of how we teach our trainees responsible conduct in research. Hammer home the importance of critical reading and careful inspection of all presented data. Teach skepticism.

But please, spare me the hyperbole. The woe-is-me crowd needs to spend a bit of time in self-reflection on where the problems with the amyloid cascade hypothesis really lie and how we can best move forward.

P.S. It’s important to add that while the *average* effect on the AD field was modest, I recognize that the damage was not uniformly distributed. There were students or postdocs who lost precious time in labs chasing this rainbow & paid a disproportionately heavy price.