5 ms·

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 mol

by DavidSJ 4mo ago

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 4mo ago
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/ https://pubmed.ncbi.nlm.nih.gov/25743013/
- DavidSJ 4mo ago
  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.

by DavidSJ 4mo ago

pcrh 4mo ago

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/ https://pubmed.ncbi.nlm.nih.gov/25743013/

DavidSJ 4mo ago
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.