Copper transport drug restores memory and clears toxic Alzheimer's proteins

That's fair. I responded to hostility with hostility. Perhaps I should have ignored the comment or just responded kindly despite the hostility.

But without any training in experimental methodologies, molecular biology, protein mechanics, pharmacology, or any of the other specialized fields that make up the world of Alzheimer's research, how do you view yourself as qualified to make that conclusion? What body of knowledge are you drawing on to conclude that the experts' reasoning is sound, they are properly controlling their experiments, they are drawing the correct conclusions based on the underlying mechanics? AFAIK even people who do meta-analyses are qualified in the field they are doing the analysis for.

This is a reasonable challenge. I won't and shouldn't be able to convince you that my process was satisfactory, but I'll describe it anyways.

I agree that I don't have the qualifications to check whether, for example, a particular cryo-EM study was conducted properly. But I can check whether those who do have such qualifications disagree on the methodology or findings of that particular study. There's a lively debate within the Alzheimer's research community; it's not hard to find dissenting opinions on just about anything, and I actively seek them out, and when such disagreement exists, I avoid weighting any evidence too heavily, unless the disagreement is about broader matters of synthesis or specific statistical or methodological questions in which my non-biological scientific background permits me to reach my own conclusions.

I am also careful not to heavily weight a single assumption-laden preclinical study conducted by a single lab, for example, but instead to look for "smoking gun"-style evidence, in those few cases that it exists, or to look at the bulk of evidence across many studies from many labs, where the specific conclusions do not seem to be seriously in doubt by experts. In general, I've been skeptical, considering alternative explanations wherever it seemed crucial to the bigger picture, and avoiding trusting anything that seemed like it involved knowledge which was heavily in the weeds on stuff that I couldn't understand. I had a personal motivation to understand the genuine truth here, and enough scientific background that I usually know when I'm out of my depth on a specific matter.

I think it's reasonable of you to say: that all sounds well and good, but I just don't know your process well enough to trust it, and you don't have formal qualifications on the matter, so I'll ignore what you say. I certainly wouldn't expect you to take anything on my authority. I see my article essentially as an act of science journalism, and scientific journalists often lack formal training in the field they report on. You can read it and see if the reasoning makes sense and the evidence is convincing, or you can reasonably ignore it and fall back on expert opinions.

I did the investigation precisely because the majority expert viewpoint was being called into question by a lot of non-experts, and I had a personal motivation to find out, genuinely, whether this critique was warranted. If you don't have that motivation, then it's probably not worth your time to do the same. I did, and I came away satisfied.

Thanks, great challenges.

One may then ask, what is being remedied in the many, many, studies that claim to successfully target amyloid toxicity in mice? And is this relevant to the processes that occur in AD?

I don't think studies rescuing cognitive deficits in amyloid-only mice are convincing evidence for the amyloid hypothesis, precisely because we know amyloid is not the proximate cause of neurodegeneration in actual Alzheimer's disease, and that proximate cause does not exist in those mice.

In other words, these mice are not faithful recapitulations of the full disease. They have their amyloid production turned up so far that their amyloid pathology seems to cause cognitive deficits, but that's not what's happening in humans. They are, at best, a good vehicle for testing specific narrow hypotheses about amyloid production and clearance. The field has largely moved on from amyloid-only mice as a direct predictor of clinical efficacy, and that was the right call.

Human pathology studies are limited in ability to determine causal agents because they are primarily observational, i.e. they find correlations, show that changes in certain other proteins or processes are associated, such as tau that you mention, inflammation, etc. Or as you mention, show that the pathological hallmarks of AD have a stereotypical order of appearance.

Here is some data in living humans, besides genetics, that has relevance to causation, in my opinion:

- The location and severity of amyloid pathology is a poor spatiotemporal match to the sites of neuronal volume loss, and to the severity and nature of clinical deficits. However, the location and severity of tau pathology is a very good match to both of these things. Of course, since these observations are correlational in nature, they don't absolutely prove a specific causal theory. But they do rule out, for example, the idea that amyloid is proximately connected (by which I mean nearby somewhere in the causal graph) to the process of neurodegeneration, whereas tau seems to be very proximately connected. From this observation alone tau could be downstream or sidestream rather than upstream, but it does then suggest that whatever causes tau pathology is itself upstream of neurodegeneration, since correlations always have a cause (the correct statement that "correlation ≠ causation" simply means "correlation between A and B does not imply that A causes B", but the explanation must be either A causes B, B causes A, or C causes both A and B).

- Anti-amyloid antibodies which remove plaque in humans cause downstream reductions in tau pathology in humans, and, separately, have clinical benefits in those humans.

- The spatiotemporal progression of amyloid and tau pathology is highly consistent with the hypothesis that amyloid pathology greatly worsens the tau pathology, but not vice versa. And there's not an alternative explanation I've come across for this fact than that amyloid pathology worsens tau pathology.

All of the above facts are generally true in combined amyloid+tau mouse models as well as in vitro human cell studies, which is some reason to believe these are closer to faithfully recapitulating the disease than the amyloid-only models. Once we believe that, we can then do more causal interventions on those models which we couldn't do in humans, and learn more about causality. For example, we know that intentionally worsening amyloid pathology in amyloid+tau mouse models also causes tau pathology and neurodegeneration to worsen in mouse models. And because these models look closer to the full disease than the amyloid-only models, this is at least relevant causal evidence, though we always have to be open to the possibility that the disease models are still missing some important elements.

I'm not aware of an alternative hypothesis to the (ATN) amyloid → tau → neurodegeneration model which synthesizes all of the above facts, along with the genetic evidence for amyloid's causal role which you referred to. By contrast, I'm not aware of any evidence inconsistent with the ATN model.

Yes, there is a clear sequence of how AD pathology develops, starting with amyloidopathy and progressing to tauopathy, but 1) there is as yet no established molecular connection between the two, and 2) one should not conflate pathology with disease mechanisms.

So, taking the amyloid hypothesis itself (putting presenilin aside for the time being).

We know that mutations in APP do cause AD. How? And if amyloid is not the "proximate" cause of AD, how do mutations in APP cause AD? Include in this Down syndrome, where >90% of cases develop early onset AD by age 50. They have an extra copy of APP that is not mutated.

Furthermore, people can accumulate large amounts of amyloid in the brain without having any notable dementia.

Adding tau to the equation does not help much in explaining how APP mutations cause AD. All people have tau. Furthermore, mutations in tau do not cause AD, they cause different neurodegenerative diseases (e.g. frontotemporal dementia).

Combining APP mutations with presenilin mutation and/or tau mutations in mice does lead to worse outcomes, but the same could be said for combining any other random set of neurodegeneration-associated gene mutations.