There’s something that’s been nagging me about Alzheimer’s research. It started after Charles Piller’s exposé in Science, Blots on a Field. If you haven’t read the article, it details alleged data fabrication from a lab in Alzheimer’s research and claims it threatens the reigning theory of what causes the disease: the amyloid hypothesis. This is a bit of an exaggeration; I won’t go into detail here, but Derek Lowe’s post summarizes the situation beautifully in the context of the broader Alzheimer’s landscape. And it contains this gem:
“…if you’d time-traveled back 30 years and told *me* (while I was working in the field) that we’d still be arguing about the amyloid hypothesis itself in 2022, I would have been profoundly displeased, to put it judiciously.”
– Derek Lowe, In the Pipeline
While the amyloid hypothesis has notched a recent win with lecanemab’s preliminary-but-positive phase 3 data, we indeed are still arguing about the amyloid hypothesis. What confuses me in particular is: we are still arguing about the amyloid hypothesis as if amyloid is the starting point, or cause, of Alzheimer’s.
To get an idea of this, think about how hypotheses in Alzheimer’s are presented. You have the amyloid hypothesis, which holds that beta amyloid accumulates outside of cells and gunks things up, causing stress and neuron death. You have the tau hypothesis, which argues that it’s actually aberrantly phosphorylated tau that forms NFTs (neurofibrillary tangles, not the other kind) and drives neuron death. Then you have the infection hypothesis, which posits that some kind of infection (such as herpesvirus or P. gingivalis), triggers inflammatory response that drives the development of Alzheimer’s. And similarly, some hypothesize that that chronic exposure to high levels of copper or sleep deprivation may drive development of the disease. See any differences between these?
Listing these hypotheses side-by-side suggests they are mutually exclusive and conflates “mechanism” of disease with “cause” (or “pathogenesis”).1
What do I mean? Let’s look at another disease, Type 1 diabetes, as an example. In Type 1 diabetes, something causes the immune system to destroy the insulin-producing beta cells in the pancreas, usually somewhere in infancy or childhood. In this disease, the “mechanism” is loss of the beta cells, which leads to the inability to produce insulin and subsequently control blood sugar. But the “cause” of disease is….a viral infection? Overactive immune system? We don’t definitively know yet.
There are diseases where cause and mechanism are the same. Monogenic genetic diseases come to mind, like cystic fibrosis and Duchenne muscular dystrophy. In these diseases, we’ve identified mutations in a gene as the cause of disease, while expression of this mutated gene into dysfunctional protein is the mechanism of disease. But aside from the APOE variants, which account for ~50% of the risk, I didn’t find much else in the way of monogenic drivers in Alzheimer’s (except for things like PSEN, but those only account for very rare familial forms).
Why does this distinction matter? Well, thinking of amyloid as the cause of disease may limit the types of scientific questions we ask, and which experiments we fund and run. If we hypothesize that amyloid causes Alzheimer’s, then we focus deeply on figuring out what amyloid is, how it works, and how we can prevent it from being made. But in our focus we fail to explore alternative potential causes. And if amyloid isn’t the cause or the mechanism of Alzheimer’s, we miss discovering the cause altogether.
One could argue that thinking of amyloid as the cause of Alzheimer’s is the only practical path for drug development in a disease that spans decades and is frankly, really f**king hard to study. After all, we developed effective treatments even we didn’t know the cause of Type 1 diabetes. But Type 1 diabetes is a disease where we’re adding in something that’s missing – something I think is easier to do in therapeutic development. In Alzheimer’s, we appear to be trying to remove something, when we have no clear understanding of what is causing this something in the first place – a much more difficult objective.
This conflation of “cause” and “mechanism” in Alzheimer’s reminds me of the Streetlight Effect and the old joke that comes with it:
A policeman sees a drunk man searching for something under a streetlight and asks what the drunk has lost. He says he lost his keys and they both look under the streetlight together. After a few minutes the policeman asks if he is sure he lost them here, and the drunk replies, no, and that he lost them in the park. The policeman asks why he is searching here, and the drunk replies, “this is where the light is”.
David H. Freedman (2010). Wrong: Why Experts Keep Failing Us, via Wikipedia (where someone made a valiant attempt to add a picture and picture description to the article).
Maybe changing our view of amyloid and tau from “cause” to “mechanism” would be illuminating.
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1 I am being a little liberal with language here, because you could say that some upstream environmental factor combined with genetics causes formation of amyloid or tau, which in turn causes Alzheimer’s. But I think making the distinction is still relevant as useful as we think about where we focus research.
Natalie Jing Ma, PhD 