[DavidSJ]

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].

This is interestingly similar to the Arctic Mutation, and in the same codon no less: no plaque, but still autosomal-dominant AD due to an APP mutation. I had previously taken the Arctic Mutation to be evidence that it's not plaque per se, put more likely protofibrils (which are components of plaques in normal AD, and still present under the Arctic Mutation) or precursor aggregates which are pathogenic. The fact that the Osaka Mutation blocks protofibril formation underlines the uncertainty, that you and I agree exists, on the detailed molecular mechanisms. I would be inclined to point then to oligomers, but you say the oligomers are found at far too low concentrations to be relevant — what's your source for this?

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.

Not only APP, but also PS1+PS2 mutations of course, can cause ADAD, and the relevant mutations all seem to cause more Abeta42 production. In the sporadic case, production usually seems unchanged, but clearance is usually impaired (especially with ApoE4). What they all seem to have in common is amyloid production or clearance. I'm curious if you know of another pathway they have in common besides this. Otherwise it's hard to see what the alternative hypothesis is, which could explain the etiology of seemingly highly-similar disease trajectories (ADAD + sporadic AD).

I’ll add as an addendum: APP mutations do cause neurodegeneration in mice, if those mice are combined amyloid+tau models. This seems most faithful to the human disease.

[pcrh]

P.S.

As you have demonstrated an interest in this topic, but are not an active researcher, I suggest that you become familiar with Alzforum [www.alzforum.org]. It provides reputable summaries and comments from leading researchers on topical issues and papers in Alzheimer's and related neurodegenerative diseases.

They're still fairly technical, but not as dense as the original papers. Here is an example related to our discussion: https://www.alzforum.org/news/research-news/app-c-terminal-f...

[DavidSJ]

I've been a regular reader of Alzforum, and cite multiple of their articles in the blog post that was linked up above. https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

[pcrh]

Thanks for the article.

I actually read your article some time ago, having found it via SSC. One comment I would make is that the pathology and genetics of AD implicate APP without much doubt. In the field, there isn't much argument against it, even by those who work on tau. Divergences in opinion more often focus on which is the better target for drug therapy.

For example, Derek Lowe's articles on AD do not argue against an APP-tau-neurodegeneration pathway (I am a regular reader of his blog), but argue that targeting amyloid is unlikely to work as a drug therapy. This argument is sometimes extended by Lowe and others to questioning whether Aβ per se is the agent that triggers the downstream effects of either mutating APP or otherwise disrupting its biology. It is possible that Aβ is a by-product of the "true" APP-triggered pathway, see the arguments in favor of C-terminal fragments I linked to earlier.

A fundamental problem the field faces is that it is difficult to experimentally induce actual AD in animals, and so it is difficult to scientifically test hypotheses as to what might cause it. Compare perhaps to something like diabetes. Exactly why mice do not develop realistic AD is unknown.

In addition, there have been literally hundreds of publications (minimum 300) claiming to reverse "Alzheimer's disease" in mice, and the only ones that have lead to any kind of meager success are those using the antibodies. The arguments made in the 2010 review below by Zahs and Ashe [0] remain mostly true sixteen years later.

The recent clinical trials, e.g. Lecanemab, are of interest not only because they might provide at least some benefit, but also because they might represent the first actual scientific experiments showing that removing Aβ can ameliorate the disease, even if only slightly because of the late stage at which they have so far been tested.

Currently ongoing trials using anti-Aβ antibodies and targeting earlier phases of the disease in those with inherited mutations are of keen interest. If these demonstrate clear prevention of disease progression, then the Aβ hypothesis can be considered tested and proven. If not, then the Aβ hypothesis should be abandoned. This would however still not disprove an APP-focused hypothesis.

[0] 'Too much good news' - are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer's disease? https://alzped.nia.nih.gov/sites/default/files/2022-09/zahs....

[pcrh]

No APP-alone mouse gets neurodegeneration resembling that seen in the human AD brain, i.e. with so-called "neuritic" plaques, tauopathy, spongiopathy and widespread neuronal death.

This is why researchers now most often use the 5XFAD mouse, which has APP with three mutations, and presenilin with two mutations (hence 5 FAD mutations) [0]. Note however that mutated presenilin alone is enough to cause neurodegeneration in mice, such mice however do not accumulate amyloid, which is why mutated APP in added to make the pathology more "realistic".

As to Aβ42, there are mutations in APP which cause familial AD, but produce exclusively Aβ40, e.g. APP A673V [1]. Note also that most studies report alterations in the ratio of Aβ42 to Aβ40, precisely because effects on the levels of Aβ production are inconsistent across APP mutations.

Nevertheless..... and despite my obvious skepticism towards the amyloid toxicity hypothesis, the mutations in APP that cause AD all cluster in or near the region of the protein that is Aβ. There must be a reason for that. It is also in contrast to presenilin, where the mutations are distributed throughout the molecule, indication a loss of presenilin function causes AD.

One alternate explanation to Aβ or oligomer toxicity is proposed toxicity of the immediate precursor to Aβ, i.e. the APP C-terminal fragment (CTF), see for example the recent paper below and references therein [2].

[0] https://www.alzforum.org/research-models/5xfad-b6sjl

[1] A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis https://pmc.ncbi.nlm.nih.gov/articles/PMC2728497/

[2] APP β-CTF triggers cell-autonomous synaptic toxicity independent of Aβ https://pmc.ncbi.nlm.nih.gov/articles/PMC12017768/

[dekhn]

At this point you should just go to grad school in a molecular neurology program. You clearly have the passion for this sort of research, and it would probably be useful to immerse yourself in the process to get more experience and judgement. Grad programs in bio usually have journal clubs; bring one of your papers, and see what people think of it.