Alzheimer’s drug research is, charitably, even more of a mess than it was earlier this week. And, given the mess it was already in, that’s not easy. Nevertheless, that was the main takeaway from yesterday’s news that Biogen and its partner Eisai were halting two clinical trials of their anti-amyloid therapy — aducanumab — because, in short, neither worked.
In case you are keeping score at home, there are now more than 300 failed Alzheimer’s drugs, which is remarkable in itself, and doubly so when you consider that most of these drugs are based on a single theory, the so-called “amyloid hypothesis”.
And what is the amyloid hypothesis? Here is a summary from Science on this now decades-old theory that isn’t working very well:
[Alzheimer’s] is caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.
In short, to this way of thinking, AD is a sort of dental plaque on brain tissue. If enough forms, and you don’t scrape it off and prevent more from forming, bad things happen to brain function. And there is plenty of evidence of amyloid proliferation in the brains of AD patients, so the theory has that going for it. Further, there is an obvious mechanical connection that can be made between brain function and the presence of amyloid plaques. So, you can see the appeal of amyloid theory.
The trouble is, as is the case so often in medicine, a bioplausible mechanistic cause, when treated, doesn’t change the outcome. Knees with meniscus tears can be painful, but the tear is often not the cause, etc. Experimental drugs have, to varying degrees, inhibited the formation of amyloid plaques to no avail, with patient outcomes largely indistinguishable from those of untreated patients.
Rather than diving deeper into the science, however, I’m more intrigued, at least philosophically, by why the amyloid hypothesis hasn’t been abandoned. Are 301 trials required? 302? What constitutes plausible negative evidence that would cause researchers at pharma companies to abandon this bioplausible theory of AD causation and progression?
In broad terms, this is a deep question, one that has puzzled scientists and philosophers for as long as both have existed. Perhaps the best-known example of an attempt to answer the question is that of Karl Popper, who, to vastly simplify his model, proposed that science proceeds through definite tests and falsification. All positive results are provisional, capable of being demolished if the right test comes along that falsifies a key element of the research.
The trouble is, of course, that isn’t really the way science works, as aducanumab and its predecessors’ failures show. If the amyloid hypothesis could be overturned by a well-crafted negative experiment (or 300), one would think that would have happened by now, which it demonstrably hasn’t. And it isn’t for want of bioplausible alternative approaches to Alzheimer’s therapy, of which there are now many.
Thomas Kuhn would argue that this is exactly what we should expect in a field as inherently pack-oriented and emotional as science. He believed that science is a social endeavor and that one of the primary reasons why hypotheses aren’t abandoned, despite overwhelming evidence of their wrongness, is that scientists hold tightly to cherished beliefs, despite them having been falsified over and over again.
His is not the only non-Popperian view, of course. Imre Lakatos vomited, a little, at Kuhn’s idea that the best way to understand science was as a kind of trend-driven teen fashion. Lakatos argued, instead, that research programmes should be thought of as “progressive” or “degenerating”, and no single experiment (or even collection of experiments) could turn a progressive programme into a degenerating. Instead what happened, to his way of thinking, was the scientists former “protective belts” around the “hard core” of the theory, leaving its main predictions intact in a way that allowed continued research to be conducted.
This is where we are at, I think, with the amyloid hypothesis. There is still a hard core to the programme, with no-one denying the connection between plaques and AD, but there is increasing uncertainty about what to do with that information. As one researcher said this week, it is like “…blowing out a match (amyloid plaques) after the forest (the brain) is already burning (suffering the death of neurons and destruction of synapses)”.
To this way of thinking, amyloid-targeting therapies would work, if only they were delivered sooner. Fair enough, but short of having asymptomatic patients at high risk on such therapies from age 50 onward, it is hard to imagine where one goes from here.
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