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.)