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.
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.