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/
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/