Recently, a scandal broke in the field of Alzheimer’s research. Sylvaine Lesné, an associate professor at the University of Minnesota was accused of falsifying image data in a series of research articles, including a seminal paper that identified a particular molecule as being instrumental in cognitive decline. A lot of the coverage of this latest scandal has focused on something called the “Amyloid Hypothesis“, with some pretty dramatic headlines that imply that decades of work, including numerous failed drug trials, were based on a single paper written by a fraudster. Things seem to be calming down a little now with cooler heads and more measured coverage, for example, see this piece on AlzForum.
Accusations of research fraud are not new. Almost a decade ago, Paul Brookes, an associate professor at the University of Rochester had a short but dramatic career as a self-appointed, anonymous image sleuth, before he was doxed and stopped blogging. Today, there are a number of individuals that voluntarily investigate the work of others to identify possible misconduct, the best known of which is Elisabeth Bik, who publishes her work on her blog Science Integrity Digest.
So why did this case set off what looked like a bit of a moral panic? Perhaps it’s to do with the high profile nature of Alzheimer’s disease and frustration at the failure to develop truly disease modifying treatments, perhaps it’s that with an aging population, there is fear that the clock is ticking on a public health crisis that will result in a societally crippling financial burden. These factors are important, as they add even more pressure to researchers struggling to make names and careers for themselves in the face of a toxic mix of perverse incentives that erodes research reproducibility and integrity.
I propose that there is another structural problem, beyond the reproducibility crisis that inflamed this particular situation — a form of scientific tribalism between two groups that disagree on which protein is the true cause of dementia in Alzheimer’s.
The alleged fraud and its overstated consequences
The research article in question was published in 2006. Lesné was the first author on it while he was working in Karen Ashe’s lab at the University of Minnesota, and he is currently an Associate professor with his own lab, also at Minnesota. It is worth noting that Ashe herself is not under investigation and no image manipulation has been found in any of her papers where Lesné was not an author. Lesné was studying TG2576 mice, which were developed by Ashe. They overexpress a mutant form of Amyloid Precursor Protein (APP), which leads to the accumulation of protein deposits in the brains of the mice, and an associated loss of cognitive function. The importance of APP and the protein deposits whose main component is called Amyloid-𝝱 (A𝝱), was not novel to Lesné’s or Ashe’s work. The so-called Amyloid Hypothesis emerged in the early 90s. In fact, the first observation of deposits, or plaques, in the spaces between neurons (along with deposits inside neurons called tau tangles) was made by Alois Alzheimer and Emil Kraepelin at the beginning of the 20th century. What Lesné claimed to have observed is that a version of A𝝱 — called A𝝱*56 — which can float around and diffuse through people’s brain was the ‘smoking gun’ that was poisoning the neurons and causing cognitive decline. He wrote that he had shown this by showing that concentrations of A𝝱*56 in the brains of TG2576 mice directly correlated with loss of memory function. The thing is, he’s far from the only person claiming that soluble oligomeric species of A𝝱 are the root cause of the disease. Particularly at the time, it was a hot topic in the field with active discussions about whether it was dimers, trimers, or some other species that was responsible.
In short, even if Lesné had never run a western blot in his life, we’d still have a significant body of research pursuing the Amyloid Hypothesis, looking at oligomers, and trying to design drugs to target Amyloid. The fraud of which he’s accused of is terrible if eventually proven to be true, but to pin decades of blind alleys on this one piece of research, is overstating its importance.
A schism in Alzheimer’s research
Along with A𝝱, the other protein that causes so much trouble in Alzheimer’s disease is called “tau”. It’s the major constituent of the tau tangles inside neurons that I mentioned earlier. Ever since those first observations that Alzheimer and Kraepelin made, researchers have been trying to understand the role of both of these proteins and how they might be connected. Something very strange has happened along the way.
Driven by a need to be right, publish frequently, and have impact in order to impress funding, hiring, and tenure committees, researchers are incentivized to adopt a position of trying to prove themselves right about their ideas. Since the way you rigorously test a hypothesis is to try to prove it wrong, these conditions create downward pressure on rigor. They also incentivize political behaviors like aligning yourself with those with power, and tearing down competitors’ ideas, rather than approaching all work in a spirit of open inquiry. The result can be tribalism.
I was personally involved in Alzheimer’s research at the time when Amyloid oligomers were gaining traction. At the time, there was already a divide in the field. An astute observer of human behavior whose name is lost to history coined the labels 𝝱aptists and Tauists to describe the two groups. The religious connotations of those nicknames is obviously not accidental. Researchers who work on tau have in the past publicly referred to the Amyloid ‘cabal’ or even Amyloid ‘mafia’. Some researchers have complained of a stranglehold on the field that prevents promising ideas involving tau from getting funded. I don’t know how much truth there is to such accusations, but the fact that they’re made at all, sometimes in public venues, is evidence of unhealthy dynamics that certainly aren’t accelerating progress towards curing the disease.
What can be done about tribalism?
I don’t wish to paint an overly critical picture of the field of Alzheimer’s research. Over time, the schism in the field has become less fractious and increasingly, models are favored that seek to account for the role of both proteins. On the other hand, when internal discussions within fields become so fractious that people lose objectivity, arguments spill out onto social media and the press and undermine both progress and public confidence in science.
Something needs to change, but what? It’s tempting to argue that more transparency, open data, or better quality control will prevent fraud, but while incentives are the way that they are, tribalism, lack of rigor, and even fraud, being symptoms of the same underlying structural problems, are almost inevitable. What needs to happen is a change in incentives to support and enable cultural changes. When researchers are solely rewarded for the rigor and transparency of their work, rather than also required to be lucky, cut enough corners, or become aggressively tribal in defending their ideas, perhaps we’ll see fewer of these scandals.