All of AβMale's Comments + Replies

There are actually three amyloid antibodies that have shown some success: aducanumab (Aduhelm), lecanemab (Leqembi), and donanemab. I think the FDA approval of aducanumab was absolutely the right decision, though it’s far from a miracle drug.

I spent about six months of my life buried in the Alzheimer literature. There’s a mountain of evidence for this hypothesis. Take a look at my previous comments if you’re curious.

1ChristianKl
There is a lot of drug development based on that theory and most of it came up empty and the one that didn't came up empty was Abuhelm which is widely seen as one of the worst FDA drug approvals of recent years.  

I wrote about this here:

[T]his error strikes me as … emblematic of a certain common failure mode within the rationalist community (of which I count myself a part). This common failure mode is to over-value our own intelligence and under-value institutional knowledge (whether from the scientific community or the Amazon marketplace), and thus not feel the need to tread carefully when the two come into conflict.

In that comment and the resulting thread, we discuss the implications of that with respect to the rationalist community’s understanding of Alzheimer’s... (read more)

3tailcalled
Potentially relevant: Random facts can come back to bite you.
2Noosphere89
Basically, this is essentially reframing the overuse of the inside view and under using the outside view, and I think this struck truer to my objection than my answer did. And yeah, John Wentworth ignored the literature and was wrong, and since John Wentworth admitted it was cherry picked, this is non-trivial evidence against the thesis that Goodhart is a serious problem for AI or humans. Though it also calls into question how well John Wentworth's epistemic processes are working.

Update today: Biogen/Eisai have reported results from Lecanemab’s phase 3 trial: a slowing of cognitive decline by 27% with a p-value of 0.00005 on the primary endpoint. All other secondary endpoints, including cognitive ones, passed with p-values under 0.01.

Not a ton.

I'd also recommend this article, including the discussion in the comments by researchers in the field.

A crucial distinction I'd emphasize which is almost always lost in popular discussions is that between the toxic amyloid oligomer hypothesis, that aggregates of amyloid beta are the main direct cause of neurodegeneration; and the ATN hypothesis I described in this thread, that amyloid pathology causes tau pathology and tau pathology causes neurodegeneration.

The former is mainly what this research concerns and has been largely discredited in my op... (read more)

Note I've edited the third-to-last paragraph in the above to remove an overly-strong claim about the four antibodies I didn't discuss in detail.

In brief, the main reason I don't think the argument works that autosomal-dominant Alzheimer's has a different etiology than sporadic Alzheimer's is that they look, in so many respects, like essentially the same disease, with the same sequence of biomarkers and clinical symptoms:

  1. Amyloid pathology starts in the default mode network, and gradually spreads throughout the brain over 15-20 years.
  2. It eventually reaches the medial temporal region, where Primary Age-Related Tauopathy is lying in wait.
  3. At this point, tau pathology, a prion-like pathology which in Alz
... (read more)
2Hyperion
I happened to be reading this post today, as Science has just published a story on a fabrication scandal regarding an influential paper on amyloid-β: https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease I was wondering if this scandal changes the picture you described at all?
2johnswentworth
Thanks, that was helpful!

A distinction is made in the literature between preclinical Alzheimer's (the presence of neuropathology such as amyloid-β, without clinically detectable cognitive symptoms) and clinical Alzheimer's (a particular cluster of cognitive symptoms along with the neuropathologies of Alzheimer's). It's currently believed that Alzheimer's has a 15-20 year preclinical phase, the duration of which, however, can vary based on genetic and other factors.

In the case of the mutations I mentioned (which are early-onset causing), clinically-detectable cognitive decline typi... (read more)

1johnswentworth
I'd be interested to read that. (Apologies for lack of citations in the below, I don't have them readily on hand and don't want to go digging right at the moment.) You're right that I never went that deep into the Alzheimer's literature; it's certainly plausible that I overlooked a cluster of actually-competently-executed studies tying Aβ-related genetic mutations to robust dementia outcomes. I did look deeply into at least one study which made that claim (specifically the study which I most often found at the root of citation chains) and it turned out to diagnose using the presence of plaques, not dementia. But that was a paper from the early 90's, so maybe better results have come along since then. However, the absence of evidence for Aβ causing Alzheimer's was not the only thing pinning down my beliefs here. I've also seen papers with positive evidence that Aβ doesn't cause Alzheimer's - i.e. removing plaques doesn't eliminate dementia. And of course there's been literally hundreds of clinical trials with drugs targeting Aβ, and they pretty consistently do not work. So if there is a cluster of genetic studies establishing that Aβ-related mutations are causal for dementia, then the immediate question is how that squares with all the evidence against causality of Aβ for dementia. If the early-onset autosomal dominant version of the disease is in fact a different disease, that would answer the question, but you apparently think otherwise, so I'm curious to hear your case.

I apologize if this is piling on, but I would like to note that this error strikes me as very similar to another one made by the same author in this comment, and which I believe is emblematic of a certain common failure mode within the rationalist community (of which I count myself a part). This common failure mode is to over-value our own intelligence and under-value institutional knowledge (whether from the scientific community or the Amazon marketplace), and thus not feel the need to tread carefully when the two come into conflict.

In the comment in ques... (read more)

9anonymousaisafety
I think one reason that this error occurs is that there's a mistaken assumption that the available literature captures all institutional knowledge on a topic, so if one simply spends enough time reading the literature, they'll have all requisite knowledge needed for policy recommendations. I realize that this statement could apply equally to your own claims here, but in my experience I see it happen most often when someone reads a handful of the most recently released research papers and from just that small sample of work tries to draw conclusions applicable that are broadly applicable to the entire field. Engineering claims are particularly suspect because institutional knowledge (often in the form of proprietary or confidential information held by companies and their employees) is where the difference between what is theoretically efficient and what is practically more efficient is found. It doesn't even need to be protected information though -- it can also just be that due to manufacturing reasons, or marketing reasons, or some type of incredibly aggravating constraint like "two hoses require a larger box and the larger box pushes you into a shipping size with much higher per-volume / mass costs so the overall cost of the product needs to be non-linearly higher than what you'd expect would be needed for a single hose unit, and that final per-unit cost is outside of what people would like to pay for an AC unit, unless you then also make drastic improvements to the motor efficiency, thermal efficiency, and reduce the sound level, at which point the price is now even higher than before, but you have more competitive reasons to justify it which will be accepted by a large enough % of the market to make up for the increased costs elsewhere, except the remaining % of the market can't afford that higher per-unit cost at all, so we're back to still making and selling a one-hose unit for them".
3johnswentworth
A priori, before having clicked on your links, my guess would be that the studies in question generally diagnose Alzheimer's by the presence of amyloid-β deposits. (That's generally been the case in similar studies I've looked into in the past, although I haven't checked the exact studies you link.) If they're diagnosing based on the presence of amyloid-β, then obviously amyloid-β producing mutations will cause an Alzheimer's diagnosis. The problem is that this diagnosis doesn't reflect real Alzheimer's, i.e. it doesn't necessarily involve dementia. We would expect such things to find strong, extensive evidence of causality. The problem is that it's extensive evidence of the mutations causing amyloid-β plaques, not dementia. (Also, a warning: this is exactly the sort of detail which overview articles tend to overlook and misstate - e.g. an overview article will say something like "so-and-so found that blah causes dementia" when in fact so-and-so were diagnosing amyloid plaques, not dementia. One does need to check the original papers.)
3Ben Pace
In general corrections are good contributions, thanks for your object-level points.