[pcrh]

I have direct experience of research into Alzheimer's disease, including specifically surrounding the amyloid cascade hypothesis.

The strength of the amyloid hypothesis is that it is currently the only way to unify early onset AD that is caused by mutations in APP and presenilin with the pathology of both early and late set AD.

The weakness is that experimental mice expressing mutated APP do not get neurodegeneration, despite showing amyloid accumulation and behavioral defects.

Mice expressing mutated presenilin in contrast do get both behavioral defects and neurodegeneration, despite showing no accumulation of amyloid.

"Perhaps mice are different" is the usual response/excuse.

This defense is considerably weaker now, given the very modest benefits of removing amyloid from the human brain, as shown in recent clinical trials.

So.... when considered rigorously, the amyloid hypothesis remains to be proven.

However, it will always have its supporters until there is an alternate explation for the convergence of mutations in APP and presenilin on precisely that region of APP that generates amyloid.

[DavidSJ]

Those are amyloid-only mice. It's an amyloid+tau disease, with tau the proximate cause of neurodegeneration. Normal mice don't get tau pathology, whereas even healthy human beings do, however it stays localized until the presence of widespread amyloid pathology.

Causal intervention on amyloid+tau mice is consistent with causal mediation from longitudinal human neuroimaging data: the amyloid pathology greatly accelerates tau pathology, and then this causes neurodegeneration.

[pcrh]

I appreciate your comment. However, a straight-forward test of the hypothesis that amyloid is the toxic (etiological) agent in AD fails when tested in mice.

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?

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.

However, the only human studies that can demonstrate cause in AD are genetic studies.

[DavidSJ]

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.

[pcrh]

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.

[DavidSJ]

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.

I agree that the specific molecular mechanism(s) is/are currently unknown. I've seen a number of proposals, but to my knowledge there isn't smoking-gun evidence for any one of them. But there can be causal evidence that A causes B (such as which I list) which exceeds a mere sequence of "A first, then B", and without knowing the specific mechanisms by which A causes B.

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.

A bit confused by these questions, and I suspect the confusion may have to do with the term "proximate". By "amyloid is not the proximate cause of neurodegeneration", I simply mean it is upstream, mediated by another cause (namely tau). I think that clarification answers these questions.

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

As predicted by the ATN model, at least for some time. But there is a threshold of amyloid pathology that does seem to guarantee progression to tau pathology and 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).

Sure, there are different tauopathies, each with a characteristic fold. All people have tau, but there's a specific AD tau fold emerging apparently from the locus coeruleus, then spreading to the hippocampus and entorhinal cortex, and it's this that seems heavily accelerated by the presence of amyloid pathology in humans. (By the way, a notable fact is that autosomal-dominant AD -- clearly caused by APP/PSEN1/PSEN2 mutations affecting amyloid production -- has the same tau fold as sporadic AD, even though the large majority of other tauopathies do not.)

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.

Note I didn't just say it "leads to worse outcomes". It's specifically that amyloid pathology worsens tau pathology, and then neurodegeneration occurs colocated with the tau pathology. This cannot be said for other random sets of mutations, in general.

(By the way, basically all of these points are discussed in the article I wrote which got linked above. You're under no obligation to read it but it might save us some time.)

[pcrh]

These points still don't explain how mutations in APP cause AD.

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. (One can ignore claims that this mutation increases Abeta oligomers, since the evidence is that Abeta oligomers are found at far too low concentrations in the human brain. They would have to be more toxic than ricin if they were etiological for AD). The oligomers seen on gels are an artefact, see the controversy surrounding Tessier-Lavigne).

As you state, and I agree, APP is upstream of tau in natural AD pathogenesis, but does not cause neurodegeneration in mice. So we still don't know from direct experimentation how APP leads to tauopathy and neuodegeneration. The evidence that this is through Abeta per se is tentative at best.

[0] A Second Pedigree with Amyloid-less Familial Alzheimer’s Disease Harboring an Identical Mutation in the Amyloid Precursor Protein Gene (E693delta) https://pubmed.ncbi.nlm.nih.gov/25743013/