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.