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 scientific community studying it, but very superficial engagement with the relevant scientific literature. Every single time I’ve debated the matter in detail with someone (maybe 5–10 times total), I’ve persuaded them that 1) the scientific community has a much better understanding of the disease than they realized and 2) that the amyloid hypothesis is compelling as a causal explanation. However, people in the rationalist community often have strongly-held, wrong opinions before (or in lieu of) these debates with me.
Ironically, the same thing happened in that thread: my interlocutor, John Wentworth, appreciated my corrections. However, I ultimately found the discussion a bit unsatisfying, because I don’t know that he made any meta-updates from it concerning the level of confidence that he started with without having seriously engaged with the literature.
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:
Amyloid pathology starts in the default mode network, and gradually spreads throughout the brain over 15-20 years.
It eventually reaches the medial temporal region, where Primary Age-Related Tauopathy is lying in wait.
At this point, tau pathology, a prion-like pathology which in Alzheimer’s has a very specific conformation, starts spreading from there. The tau protein misfolds in the exact same way in both forms of the disease (Falcon et al (2018). Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold), however it misfolds in a different way in the large majority of other known tau pathologies, of which there are a dozen or so (Shi et al (2021). Structure-based classification of tauopathies).
Then, neurodegeneration follows in lockstep throughout the brain with the presence of tau pathology, with cognitive deficits matching those expected from the affected brain regions. In particular, since the hippocampal formation is located in the medial temporal region, anterograde amnesia is typically the first symptom in both types of Alzheimer’s (unlike many other forms of neurodegeneration, in which other clinical symptoms dominate in the early stages).
It’s as if two bank robberies occurred two hours apart in the same town, conducted in almost exactly the same manner, and in one we can positively ID the culprit on camera. It’s a reasonable conclusion that the culprit in the other case is the same.
Some further evidence:
There has been extensive causal mediation modeling, e.g. Hanseeuw et al (2019). Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease, which so far as I’m aware always fits the amyloid → tau → neurodegeneration (ATN) model of the disease, and generally doesn’t fit contradictory models.
There have been extensive in vitro and in vivo studies showing that amyloid pathology can directly induce tau pathology (which, as mentioned above, correlates with the location and severity of neurodegeneration). He et al (2018). Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation and Lodder et al (2021). CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia are just two of dozens of examples.
The main genetic risk factors of sporadic, late-onset Alzheimer’s disease are shown to impair amyloid-β clearance or compaction (e.g. Castellano et al (2011). Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance, among many others), although through less well-understood mechanisms, often involving lipid processing, so by itself this isn’t smoking gun evidence, but it is consistent with everything else that is known.
As for the evidence from amyloid-targeting therapies, a few things can be said. I’ll focus on monoclonal antibodies, which are the most-favored approach in the research community today. I’m aware of seven such antibodies: aducanumab, donanemab, lecanemab, solanezumab, crenezumab, gantenerumab, and bapineuzumab. Of these, three have had promising, though not stellar, findings in clinical trials:
Aducanumab passed its cognitive endpoint in its phase 2 trial (Sevigny et al (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease), and one of two phase 3 trials (Haeberlein et al (2022) Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease).
Donanemab passed its primary endpoint in its phase 2 trial. Mintun et al (2021). Donanemab in Early Alzheimer’s Disease (It hasn’t yet reported from a phase 3 trial.)
Lecanemab was found, in a Bayesian analysis of its phase 2 trial, to have a 64% chance of slowing cognitive decline by at least 25% (however, the primary endpoint was an 80% chance, so it technically failed its trial). Swanson et al (2021). A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody (It also hasn’t yet reported from phase 3. [Update Sep 27, 2022: Now it has. Slowdown of cognitive decline by 27% with a p-value of 0.00005.])
In the above cases, the reduction in the pace of cognitive decline is generally around 30% or so, with a fairly wide range around that. [Removed claim about the other antibodies “almost always” showing a nonsignificant directional effect, after reviewing the data again.] Furthermore, some of the failed studies skirted the edge of statistical significance, and when they have looked at earlier vs. later intervention have typically found that earlier intervention is more effective (e.g. Doody et al (2014). Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer’s Disease).
This is all what we expect if amyloid is causally far upstream of the more proximate causes of neurodegeneration: if you only start intervention in the clinical phase, then you’re 15-20 years into the disease and the tau pathology is already active and spreading and causing neurodegeneration on its own, thus you’ve effectively taken the gun out of the shooter’s hand after they’ve already pulled the trigger. This is helpful (and in Alzheimer’s, it appears to slow decline by ~30%). On the other hand, you either need to intervene much earlier (not yet tested, although the first results from such trials are expected later this year), or in a different manner (I favor tau antibodies for the clinical phase) if you expect to do more than that.
(I know I didn’t provide references to all my claims, but I can dig them up from my notes for anything specific if you’re curious.)
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 an entire, highly-cited paper was written about it: Arboleda-Velasquez et al (2019). Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Note, however, that the typical cluster of symptoms did eventually occur.
Honestly, these particular mutations are so pervasively discussed in the literature, precisely due to their significance to the causal question, that I can tell you have not really engaged with the literature by your unawareness of their existence and the effects that they have on people.
I will readily acknowledge, by the way, that by themselves they don’t close the book on the causal question: someone could argue that early-onset, autosomal dominant Alzheimer’s due to these mutations is essentially a different disease than the much more prevalent late-onset, sporadic Alzheimer’s. While I don’t think this argument ultimately goes through, and I’d be happy to discuss why, my main point is not that there’s no residual question about the the etiology of the disease, but that the research community has intensely, intelligently, and carefully studied the distinction between correlative and causal evidence, as well as the distinction between neuropathology and cognitive symptoms. A lot of really smart, well-informed, careful practitioners work in this field, and it’s helpful to learn what they’ve discovered.
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 in Alzheimer’s disease. However, there is extensive, strong causal evidence for its role: most notably, that certain mutations in the APP, PSEN1, and PSEN2 genes deterministically (as in, there are no known exceptions for anyone living to their 80′s) cause Alzheimer’s disease, and the corresponding proteins are well understood structurally and functionally to be key players in the production of amyloid-β. Furthermore, the specific mutations in question are shown through multiple lines of evidence (structural analysis, in vitro experiment, and in vivo experiments in transgenic mice) to lead directly (as opposed to indirectly, via a hypothetical other Alzheimer’s-causing pathway) to greater production of amyloid-β.
A detailed summary of this and further evidence can be found in section 1.1 “Rationale for targeting Aβ and tau” of Plotkin and Cashman (2020). Passive immunotherapies targeting Aβ and tau in Alzheimer’s disease. A good general survey on amyloid-β production is Haass et al (2012). Trafficking and Proteolytic Processing of APP.
(My background: I have a family member with Alzheimer’s and as a result I spent five months studying the scientific literature on the subject in detail. I am posting under a pseudonym to protect my family member’s privacy.)
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.