AβMale
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In particular, Alzheimer's disease is a dual prion disease (amyloid-β and tau), and there are numerous other known prion diseases.
See Nguyen et al (2021). Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis and Shi et al (2021). Structure-based classification of tauopathies for some great detail on this.
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 disease, a disease I’ve studied in great depth. I’ve mostly found the community to have very strong opinions on that subject and disdain for the... (read more)
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 opinion since approximately 2012; the latter has a mountain of evidence in favor as I've described, and that hasn't really changed now that it's turned out that one line of evidence for an importantly different hypothesis was fabricated.
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:
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 typically starts around the age of 45, and nearly always by the age of 60. One of the only known examples in which symptoms didn't start until a person was in her 70's was so surprising that... (read more)
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 question, johnswentworth asserts, confidently, that there is nothing but correlational evidence of the role of amyloid-β... (read more)
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.