4 ms·

How did we rule out an underlying pathology that triggers toxic buildup of these substances, either as a byproduct or even as a defense mechanism (perhaps to is

How did we rule out an underlying pathology that triggers toxic buildup of these substances, either as a byproduct or even as a defense mechanism (perhaps to isolate / destroy neurons that are infected). It would seem that if cognitive decline were caused by some neurological disease and the body were fighting that, it might cause all kinds of dangerous looking things to happen to neurons. And, if you do dangerous things to neurons, perhaps you also get cognitive decline.

lazide 4y ago
It hasn’t been ruled out, it just hasn’t been able to be identified either. Some research is ongoing related to viral infection from some common viral species for instance. The problem is that we have non-destructive and reliable way to image or sample the brain at the resolutions necessary to see what is going on right now. If you can’t see or sense what’s happening until it’s too late, it’s really hard to figure out what is going on. If doing post-Mortem brain biopsies (most common way) for Alzheimer’s patients and the plaques is the equivalent of picking through the wreckage of a lost war, it’s pretty hard to figure out who was the enemy and who was collateral damage.
- mitjam 4y ago
  There are some but research into viral origins or other competing ideas seem to be marginalized and underfunded, I don‘t have first hand insights into it but read about it here https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte... and elsewhere.
- throwawaymaths 4y ago
  > we have non-destructive I think you meant to say we don't have non-destructive?
  - lazide 4y ago
    Thank you, yes. I can’t edit my comment anymore. :(
throwawaymaths 4y ago
We didn't rule it out. I worked in an Alzheimer's lab about 15 years ago. In our outside voice for Grant committees, publications, etc. We acknowledged the amyloid hypothesis but internally almost every other group meeting the postdocs and grad students disclaimed that we still couldn't rule out "common factor X". It was also morbid humor we would say "oh maybe the amyloid hypothesis is wrong" whenever something strange would come up. We only about 10% joking. It's nice to see that skepticism has finally bubbled up across the field. I like to think we were one of the more honest groups in the field -- I have post-publication corrections on my papers, the lab issued an 11-page retraction (with cautions about what not to do experimentally) when it turned out one of our lab's major findings was an artifact [0]. It's worth noting WHY the amyloid hypothesis sticks around, it's because the prion hypothesis is extremely well supported by the data (even though I think pruisner is a shady dude), so it's not a stretch to think that other amyloid diseases work in a similar way [1]. [0] the grad student who pushed through this paper is a huge scientific hero. [1] there are some subtleties though.
- throwawaymaths 4y ago
  I guess I should post a positive example of what the field (should be/should have been) doing: https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 Ms. Murray (aforementioned hero) is doing a startup these days so if you are or know any VCs that talk a good game about funding science then see if they'll throw some money her way.
zosima 4y ago
It hasn't been ruled out, but as Derek Lowe mentions, there is a good amount of genetic evidence that increased cleaving of APP and thus more amyloid-beta leads to earlier, faster and more severe Alzheimer's. And certain mutations in the amyloid-beta producing APP-cleavage machinery leads to familial dominant Alzheimer's, where the carriers will almost certainly develop early Alzheimer's. So there is not many ways around APP/amyloid-beta having some role in Alzheimer's pathology.
atombender 4y ago
Definitely hasn't been ruled out. Researchers have hypothesized that the amyloid plaques are a protective mechanism; unfortunately, we still don't know why they form. One hot area of research is currently focused on herpesviruses such as HSV1. Here [1] is a paper summarizing some of that research. The thing about viruses is that they are weird things with unexpected behaviours. For example, we are still learning about Epstein-Barr (EBV, which is another type of herpesvirus); only this year did researchers come to suspect that EBV could be responsible for MS. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/

lazide 4y ago

It hasn’t been ruled out, it just hasn’t been able to be identified either. Some research is ongoing related to viral infection from some common viral species for instance. The problem is that we have non-destructive and reliable way to image or sample the brain at the resolutions necessary to see what is going on right now. If you can’t see or sense what’s happening until it’s too late, it’s really hard to figure out what is going on. If doing post-Mortem brain biopsies (most common way) for Alzheimer’s patients and the plaques is the equivalent of picking through the wreckage of a lost war, it’s pretty hard to figure out who was the enemy and who was collateral damage.

mitjam 4y ago
There are some but research into viral origins or other competing ideas seem to be marginalized and underfunded, I don‘t have first hand insights into it but read about it here https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte... and elsewhere.
throwawaymaths 4y ago
> we have non-destructive I think you meant to say we don't have non-destructive?
- lazide 4y ago
  Thank you, yes. I can’t edit my comment anymore. :(

throwawaymaths 4y ago

We didn't rule it out. I worked in an Alzheimer's lab about 15 years ago. In our outside voice for Grant committees, publications, etc. We acknowledged the amyloid hypothesis but internally almost every other group meeting the postdocs and grad students disclaimed that we still couldn't rule out "common factor X". It was also morbid humor we would say "oh maybe the amyloid hypothesis is wrong" whenever something strange would come up. We only about 10% joking. It's nice to see that skepticism has finally bubbled up across the field. I like to think we were one of the more honest groups in the field -- I have post-publication corrections on my papers, the lab issued an 11-page retraction (with cautions about what not to do experimentally) when it turned out one of our lab's major findings was an artifact [0]. It's worth noting WHY the amyloid hypothesis sticks around, it's because the prion hypothesis is extremely well supported by the data (even though I think pruisner is a shady dude), so it's not a stretch to think that other amyloid diseases work in a similar way [1]. [0] the grad student who pushed through this paper is a huge scientific hero. [1] there are some subtleties though.

throwawaymaths 4y ago
I guess I should post a positive example of what the field (should be/should have been) doing: https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 Ms. Murray (aforementioned hero) is doing a startup these days so if you are or know any VCs that talk a good game about funding science then see if they'll throw some money her way.

zosima 4y ago

It hasn't been ruled out, but as Derek Lowe mentions, there is a good amount of genetic evidence that increased cleaving of APP and thus more amyloid-beta leads to earlier, faster and more severe Alzheimer's. And certain mutations in the amyloid-beta producing APP-cleavage machinery leads to familial dominant Alzheimer's, where the carriers will almost certainly develop early Alzheimer's. So there is not many ways around APP/amyloid-beta having some role in Alzheimer's pathology.

atombender 4y ago

Definitely hasn't been ruled out. Researchers have hypothesized that the amyloid plaques are a protective mechanism; unfortunately, we still don't know why they form. One hot area of research is currently focused on herpesviruses such as HSV1. Here [1] is a paper summarizing some of that research. The thing about viruses is that they are weird things with unexpected behaviours. For example, we are still learning about Epstein-Barr (EBV, which is another type of herpesvirus); only this year did researchers come to suspect that EBV could be responsible for MS. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/