I was thinking about the reaction to my posts over the past 48 hours, and it occurred to me that maybe they would receive a better reaction if I did a better job of demonstrating the epistemic virtues championed by the rationality community.

The all-time greatest hits for demonstrating epistemic virtue are, of course, falsifiable predictions about the outcome of an experiment that has not been conducted, could not be conducted using the resources available to the predictor, and which matter a great deal to the community assessing the epistemic virtue of the predictor.

So I thought I would post my theory of the etiology of Alzheimer's disease, along with a description of a low-cost treatment that this theoretical etiology would suggest would treat and even reverse the symptoms of this dread disease.

What? I hear the reader gasp in shocked dismay. He's doing it again? This guy really is the crank-to-end-all-cranks! And so I am, I suppose. But I invite any interested readers who care about someone who has or may develop Alzheimer's disease to test out my theory in a randomized clinical trial. If I had my druthers, I would nominate @Scott Alexander to organize the clinical trial, since he is both well-regarded by the community, and a domain expert in psychiatry, the relevant science.

Prior Work

We link to popular treatments of some important prior work to establish that this theory is grounded in up-to-date science.

https://alzheimergut.org/ is the website associated with existing research into the gut microbiome hypothesis of Alzheimer's disease.

https://github.com/epurdy/ethicophysics/blob/main/serotonin.pdf is my personal (incomplete) theory on the function of the neurotransmitter serotonin in the mammalian nervous system.

https://www.sciencedirect.com/science/article/abs/pii/S0920996417305017#:~:text=Conclusions%3A%20violent%20schizophrenia%20patients%20treated,the%20placebo%20after%20twelve%20weeks. is a description of the use of fish oil to treat schizophrenia. This is a treatment that has shown some limited success in treating schizophrenia.

https://www.quantamagazine.org/in-the-guts-second-brain-key-agents-of-health-emerge-20231121/ is a description of the relation of serotonin in the gut to glial cells in the brain.

Proposed Treatment

  • A very serious course of very serious antibiotics
  • A stool transplant from a healthy subject
  • Megadoses of EPA and DHA
  • A clinically relevant dose of a typical SSRI (Zoloft should work, Trazodone might work too. The question of Trazodone is actually kind of a crucial detail that I don't understand yet, since Trazodone is a short-term serotonin antagonist as well as (I think?) an SSRI. So animal studies would want to examine both drugs.)
  • Adequate sleep
  • A diet rich in the protein, nutrients, and micronutrients that make up the human brain. I think there is a rich existing literature investigating the question of diets that slow and mitigate the progression of Alzheimer's disease

Proposed Etiology

  • A bad gut microbiome develops, for reasons that I do not understand, and which seem irrelevant to the correctness of this theory
  • Whatever mechanism that exists in the gut to pump massive amounts of serotonin into the bloodstream and into the "second brain" in the gut are disrupted
  • The organism's neurotransmitter and neural activation profile becomes that of an animal starving to death
  • The brain relentlessly prunes itself to preserve calories in the face of this perceived impending caloric deficit
  • Presumably amyloid plaques are generated as some sort of neural scar tissue during this physiologically normal pruning process, generating the neural signature targeted (ineffectually) by the previous generation of Alzheimer's treatments
  • The brain eats itself, destroying everything of value in its quest to survive.
  • We administer the treatment proposed above
  • The brain learns from the second brain in the gut that it need not eat itself
  • The increased serotonin coming from the Zoloft, along with the EPA and DHA coming from the supplements, together with the Alzheimers diet, allows and encourages the brain to trigger neurogenesis, reversing the decline and allowing the creation and integration of new neural tissue and structures.
  • The patient lives to a ripe old age in fine neuropsychiatric health, receiving additional stool transplants and courses of antibiotics sa needed.

Thank you for your time!

New Comment
30 comments, sorted by Click to highlight new comments since: Today at 8:14 PM

Problems:

  • I'm pretty sure young starving people do not spontaneously develop Alzheimer's. (Admittedly I haven't looked into that question, but I sure do expect I would have heard of starvation as a model for Alzheimer's if it were true.)
  • On this model, I don't see any reason for Alzheimer's to be mainly correlated with age. (Note that whatever the connection is between Alzheimers and age, it has to be an absolutely ginormous effect size which completely swamps approximately-everything else. We're not talking some third-order effect of a relatively-small age-related shift in the microbiome.)

Young people forget important stuff, get depressed, struggle to understand the world. That is the prediction of my model: that a bad gut microbiome would cause more neural pruning than is strictly optimal.

It is well documented that starving young people have lower IQ's, I believe? Certainly the claim does not seem prima facie ridiculous to me.

The older you get, the more chances you have to develop a bad gut microbiome. Perhaps the actual etiology of bad gut microbiomes (which I do not claim to understand) is heavily age-correlated. Or maybe we simply do not label neural pruning induced by fake starvation perceptions as Alzheimer's in the absence of old age. 

Note that the Alzheimer's gut microbiome have induced Alzheimer's-like symptoms in young healthy mice by transferring something (tissue?) from the brain of human Alzheimer's patients to the stomach of young healthy mice; thus, I consider this particular claim (young people can get Alzheimer's) to have heavy empirical validation, if only in animal models.

https://alzheimergut.org/research/ is the place to look for all the lastest research from the gut microbiome hypothesis community.

I predict that this post will be received favorably: this is what wacky ideas that turn out to work look like. I think your proposed etiology is bunk, and you've stated your hypothesis with way too much confidence, but there seems to be some connection between Alzheimer's and the gut microbiome and your proposed treatment is quite low risk. It's the kind of thing people should try if they've got nothing better, and afaict there is nothing better.

I will publicly wager $100 against a single nickel with the first 10 people with extremely high LessWrong karma who want to publicly bet against my predicted RCT outcome.

And if people refuse to take such an attractive bet for the reason that my proposed cure sounds like it couldn't possibly hurt anyone, and might indeed help, then I reiterate the point I made in The Alignment Agenda THEY Don't Want You to Know About: the problem is not that my claims are prima facie ridiculous, it is that I myself am prima facie ridiculous.

Since you're willing to straightforwardly exchange cash for status boosts, you could offer some comparable reward for people fitting the same criteria who will publicly take your side of the bet.

OK, anybody who publicly bets on my predicted outcome to the RCT wins the right to engage me in a LessWrong dialogue on a topic of their choosing, in which I will politely set aside my habitual certainty and trollish demeanor.

I only have moderately high karma but I'd be happy to take this bet.

OK, let's do it. Your nickel against my $100.

What resolution criteria should we use? Perhaps the first RCT that studies a treatment I deem sufficiently similar has to find a statistically significant effect with a publishable effect size? Or should we require that the first RCT that studies a similar treatment is halted halfway through because it would be unethical for the control group not to receive the treatment? (We could have a side bet on the latter, perhaps.)

What would the study look like? Presumably scores on a standard cognitive test designed to measure decline of Alzheimer's patients, with four arms: control, Zoloft, Trazadone, and Zoloft + Trazadone (with all of the other components of the treatment, in particular the EPA/DHA, constant for all non-control subjects). Let me know if you have any thoughts on the study design or if I should put together a grant proposal to stsudy this.

Perhaps the first RCT that studies a treatment I deem sufficiently similar has to find a statistically significant effect with a publishable effect size?

Yeah this sounds good to me.

How will we handle the desk drawer effect, where insignificant results are quietly shelved? I guess if the trial is preregistered this won't happen...

Yes, we could require the study to be preregistered. OR to have significant-enough results - say, effect sizes greater than RCTs of the current standard treatment? (Unless the current treatments really suck, I haven't looked into it)

They really suck. The old paradigm of Alzheimer's research is very weak and, as I understand it, no drug has an effect size sufficient to offset even a minimal side effect profile, to the point where I think only one real drug has been approved by the FDA in the old paradigm, and that approval was super controversial. That's my understanding, anyway. I welcome correction from anyone who knows better.

So maybe we should define the effect size in terms of cogntiive QALY's? Say, an effective treatment should at least halve the rate of decline of the experimental arm relative to the control arm, with a stretch goal of bringing the decline to within the nuisance levels of normal, non-Alzheimer's aging, and an even stretchier stretch goal of reversing the condition to the point where the former Alzheimer's patient starts learning new skills and acquiring new hobbies.

Say, an effective treatment should at least halve the rate of decline of the experimental arm relative to the control arm

Yeah, that sounds good.

I can put together some sort of proposal tonight, I suppose.

This post looks to me like it's not living up to any epistemic virtues championed by the rationality community.

When we talk about predictions in rationality we are talking about statements that come with the likelihood of whether or not a future event happens.

You lay out a thesis, but you don't make an argument for why I should believe the thesis. You are just saying what you believe to be true and not why you believe it. 

The fact that you believe that someone would run a clinical trial because you wrote the post also suggests that you are a bit delusional about how things work. 

Oh, come on. If the rationality community disapproved of Einstein predicting the transit of Mercury, that's an L for the rationality community, not for Einstein.

I have offered to say why I believe it to be true, as soon as I can get clearance from my company to publish capabilities relevant theoretical neuroscience work.

Whether someone has epistemic virtue depends on whether they use the epistemic tools available to them. We made a lot of progress in epistemics in the last hundred years.

Well then, I submit that courage is a virtue, when tempered with the wisdom not to pick fights you do not plan to finish.

And I'm happy to code up the smartphone app and run the clinical trial from my own funds. My uncle is starting to have memory trouble, I believe.

Clinical trials are highly regulated. The median cost of a clinical trial is on the order of US$19 million. Do you have that kind of money available to run a clinical trial?

I have the courage to commit an act of civil disobedience in which I ask people caring for Alzheimer's patients to request a Zoloft and/or Trazodone prescription for their loved ones, and then track the results.

Do you think I lack the persistence and capital to organize something of that nature? Why or why not?

That setup doesn't give you a randomized control trial which is what's usually meant with the term clinical trial.

The system has a lot of incentives against doctors cooperating with illegal clinical trials. I don't think there's a notable example of anyone who pulled off a comparable trial which suggests that it's hard.

And I also have the courage to apply to Y Combinator to start either a 501c3 or a for-profit company to actually perform this trial through legal, official channels. Do you think that I will be denied entry into their program with such a noble goal and the collaboration of a domain expert?

This comment continues to annoy me. I composed a whole irrational response in my mind where I would make credible threats to burn significant parts of the capabilities commons every time someone called me delusional on LessWrong.

But that's probably not a reasonable way to live my life, so this response is not that response.

I get that history is written by the victors. I get that what is accepted by consensus reality is dictated by the existing power structures. The fact that you would presume to explain these things to the author of Ethicophysics I and Ethicophysics II simply demonstrates that you have either failed to read these documents, failed to understand what they are saying, or are simply too pigheaded for your own or anyone else's good.

I do not appreciate being called delusional, and I must ask you never to use that word in reference to me again (at least not to my face). You have my permission to use the synonyms "irrational" (for claims that you believe have poor Bayesian hygiene) or "unreasonable" (for claims or suggestions that you think do not lead to Pareto-optimal outcomes consistent with morality as it is commonly understood).

If you do continue to be condescending to me, then my response is always going to be some mostly-polite but quite direct explanation of the current location of your foot relative to the current location of your oral cavity. 

And history will not be kind to both sides of any discussion like that. I offer you a choice: continue to pooh-pooh my proposed treatment for Alzheimer's disease, and accept some wager at my proposed odds on the probable outcome of this trial when I organize it out of my own free time and my own funds, or (and I say this as politely as I know how) find some more reasonable use of the precious gift of your time on Earth than to comment on my work, my character, or the inside of my head.

https://chat.openai.com/share/068f5311-f11a-43fe-a2da-cbfc2227de8e

Here are ChatGPT's speculations on how much it would cost to run this study. I invite any interested reader to work on designing this study. I can also write up my theories as to why this etiology is plausible in arbitrary detail if that is decision-relevant to someone with either grant money or interest in helping to code up the smartphone app we would need. to collect the relevant measurements cheaply. (Intuitively, it would be something like a Dual N-Back app, but more user-friendly for Alzheimer's patients.)

The easiest way to check whether this would work is to determine a causal relationship between diminished levels of serotonin in the bloodstream and neural biomarkers similar to that of people with malnutrition.

Well that should be straightforward, and is predicted by my model of serotonin's function in the brain. It would require an understanding of the function of orexin, which I do not currently possess, beyond the standard intuition that it modulates hunger. 

The evolutionary story would be this:

  • serotonin functions (in my model) to make an agent satisficing, which has many desirable safety properties, e.g. not getting eaten by predators when you forage unnecessarily
  • the most obvious and important desire to satisfy (and neurally mark as satisfied) is the hunger for food modulated by the hormone/neurotransmitter orexin
  • the most obvious mechanism (and thus the one I predict) is that serotonergic bacteria in the gut activate some neural population in the gut's "second brain", sending a particular neural signal bundle to the primary brain consistent with malnutrition (there are many details here that I have not worked out and which could be usefully worked on by a qualified theoretical neuroscientist)
  • this neural signal bundle would necessarily up(???)modulate the orexin signal(???)
  • sustained high levels of orexin lead to autocannibalism of the brain through sustained neural pruning

Also, for interested readers, I am happy to post a more detailed mechanistic neuroscience explanation of my theory, but want to make sure I'm not breaking my company NDA's by sharing it first.