An Alzheimer's Bet Based on Biology

Alzheimer's research has been accused of being hijacked by a misleading hypothesis that only survives to enrich drug companies.  The amyloid hypothesis has been extensively critiqued, including by this essay on the blog Astral Codex Ten that looked at problems with the original paper that started (by some accounts) 30 years of misguided research.  

In response to a call for counter-arguments, David Schneider-Joseph, presented a compelling argument in favor of the amyloid hypothesis.  He even went so far as to propose a bet; that a drug targeting amyloid would achieve at least a 75% slowdown in Alzheimer's in the next 12 years.

I wouldn’t take David’s proposed bet, because I’m sure some company will find a way to gerrymander clinical endpoints to get to 75% “slowdown”.  Probably with a drug that has horrible side effects and costs north of $100,000/year.  

I would bet on the following:  the leading* therapy in 12 years will not be one whose sole intended mechanism involves amyloid production or clearance, e.g. monoclonal antibodies, small molecules, or gene editing that work directly on amyloid.  

    * “Leading” means some combination of efficacious and most widely used.

This is the important sense in which the amyloid hypothesis is wrong: it may be “correct” in some narrow biochemical sense, but it is a dead end.

In a way this is an easy bet on the status quo continuing indefinitely, because the current drugs used to treat Alzheimer's do not target amyloid.  However, I’m also bullish on emerging therapies such as creatine, lithium, calcium channels, and mitochondrial therapies including far infrared, ketones, and other ways to generally affect metabolism and autophagy/mitophagy.  Some of these might be shown to improve clearance of amyloid, but the amyloid hypothesis is not necessary or very helpful in the development of these “general" therapies.  

My prediction is based on a general model of how biology works.  Simple infectious and traumatic medical conditions seem most amenable to targeted therapies, while general conditions like mental illness, cancer, and Alzheimer’s are so complicated and depend on so many general health processes that targeted therapies tend to miss the mark.  

Ideally, we would pursue both lines of treatment, but our pharma system is biased toward patentable targeted treatments to the exclusion of all else.  The “Amyloid Mafia” is shorthand for this trend in Alzheimer’s research.  

However, even given the funding disparity between amyloid research and other treatments, non-amyloid treatments are arguably already more efficacious.  As a good Bayesian, I predict this will continue, and so this seems like a safe bet to me!