3 ms·

I'm curious how this squares up with the failure of drugs targeting beta-amyloid plaques. Despite some of these drugs being very effective at clearing Aβ plaque

by tux3 5y ago

I'm curious how this squares up with the failure of drugs targeting beta-amyloid plaques. Despite some of these drugs being very effective at clearing Aβ plaques, they don't seem to ever achieve any significant benefit in clinical trials. Reading Derek Lowe, you'd get the impression that the beta amyloid hypothesis is a formerly exciting thing of the past with a disastrous track record. >the relentless failure in this area, when amyloid plaques seemed for so long to be the most likely causative agent for the disease, is really something that makes you question things. >Add in the additional complete failures for every other attempt at the amyloid mechanism (secretase inhibitors, for example) and you start wondering if amyloid really is a cause of the disease or not Now Wikipedia is more optimistic: >The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is not conclusively established. I'm curious to see what comes out of this study, it's a very encouraging result. But it's hard to resolve this conflict of the mechanism looking great on paper, and completely failing in trials.

eightysixfour 5y ago
I only have a passing understanding, so forgive me if I get some of this wrong, but my understanding is that the beta amyloid hypothesis is "disproven" from the perspective that removing beta amyloid that has built up doesn't seem to resolve the symptoms. That is different than it isn't a causal link in the chain though. For example (making this up) I don't think we have disproven that beta amlyoid build-up causes inflammation, which actually causes the brain damage via a process that continues even once the beta amyloid is gone.
- tux3 5y ago
  What I find puzzling if the plaques are a link in the chain (as opposed to a symptom), isn't so much that beta-amyloid drugs stop short of outright resolving the symptoms, but that they don't seem to affect the progress of the disease. To continue with your example, if beta-amyloid was a major source of inflammation, and inflammation caused the damage, it'd seem reasonable to expect that removing the plaques would result in slowed cognitive decline. Strangely, this does not seem to happen in clinical trials.
- randcraw 5y ago
  As I recall, several studies have also shown that people can have high levels of amyloid-beta plaques (ABPs) in the brain and not show any signs of dementia. Between the two outcomes (ABPs exist but there's no decline, and ABPs are removed but dementia persists), the prevailing interpretation is that ABPs alone do not cause Alzheimer's. They seem to arise along with the cognitive loss, though not cause it. Tau deposits and associated neurofibrillary tangles have also been implicated in dementia, but also can be absent in those with the disease, so they too are not directly causal.
  - catlikesshrimp 5y ago
    Everything you said is still consistent with the beta amyloid theory. The plaques don't cause dementia, they are supposed to lead to damage. Once dementia sets in, there is no turning back, the neuronal network has been damaged enough and you can't replace neurons (not most of them) Dementia is the main symptom of Alzheimer. And there are other causes of dementia, too.
  - ABetaMale 5y ago
    The current most plausible perspective is amyloid-β pathology causes tau pathology which causes neurodegeneration. Thus it's not surprising that amyloid-β pathology can exist without neurodegeneration, if there is no tau pathology (or none yet). However, I have not heard of the opposite: people with cognitive decline and amyloid-β pathology but no tau pathology.
goda90 5y ago
Could it be that the amyloid-beta plaques are just a by-product of the same thing that is causing the damage in the first place?
- ABetaMale 5y ago
  That's a natural a priori hypothesis but there's extremely strong evidence that amyloid is causally upstream. For example, mutations in the enzymes or proteins involved in the production of amyloid-β (APP, PSEN1, and PSEN2), which structural analysis show have the direct effect of producing either more total amyloid-β, or more of amyloid-β 42 (the specific peptide implicated in Alzheimer's), deterministically cause Alzheimer's. That puts amyloid-β causally upstream at least in those cases, the so-called autosomal dominant variety, which are ~1% of Alzheimer's cases. The remaining ~99% of cases are less straightforward to interpret, but the disease looks essentially the same as the ~1% of cases described above: first amyloid-β builds up in the default mode network, then it spreads throughout the brain, eventually reaching the medial temporal region where primary age-related tauopathy (PART) is waiting, only then does the tau pathology spread, and neurodegeneration follows the tau pathology in lockstep. The way the amyloid-β and tau proteins misfold in autosomal dominant and sporadic Alzheimer's are the same, too, even though other tau pathologies have different tau folds. So basically, there's every reason to believe sporadic Alzheimer's is essentially the same disease as the one which we're basically certain is caused by amyloid-β.
monopoledance 5y ago
From what I got from skipping over the study, this isn't about beta-amyloid itself, but "triglyceride-rich lipoprotein" amyloid beta complexes. The amyloid beta plaques may be not cause, but symptom of the disease. Maybe the TRL-A-betas are causing the damage, get metabolized and after that the protein separates and then accumulates in the brain? The study states, the TRL-A-beta are causing inflammation, which they attribute for disease progression rather than A-beta plaque formation. > ...the findings presented in this study nonetheless support a now large body of evidence that demonstrates that the genesis of plaque is not the initiating trigger for neurodegenerative processes to be initiated, but rather, may be consequential. This study provides evidence that more subtle chronic interactive effects of peripheral metabolism of TRL-Aβ with the cerebrovasculature may be sufficient to potentially cause AD. So, clearing up A-betas may be just flushing the "damage logs".
- ethbr0 5y ago
  > This study provides, for the first time, direct evidence that hepatic expression of genes leading to the synthesis of human-Aβ is causally associated with corruption of the NVU, with cell death and brain atrophy realised. [...] Consistent with the hypothesis of increased neurovascular insult as a consequence of hepatic synthesis of TRL-Aβ, PET findings clearly demonstrated an age-associated increase in [Pittsburgh compound] uptake. We suggest that this was indicative of the marked abundance of amyloid-rich lipofuscin aggregates distributed within brain parenchyma and within vessel lumen. They definitely seem to lean into the neurovascular damage angle. I.e. liver produces amyloid-beta complexes, high levels of which result in neurovascular damage, resulting in lipids making it through and accreting in the brain. Which makes sense, as if your capillaries are less functional, how would you body clear plaques from a difficult to reach organ (the brain)?
lumost 5y ago
It's also possible that something which causes the liver to synthesize amyloids is the causative agent in alzheimers. In which case the amyloids may be a by-product.
ABetaMale 5y ago
Amyloid-targeting drugs have not failed. There are currently three — aducanumab (phase 2 trial successful, one of two phase 3 trials successful), donanemab (successful phase 2 trial), and lecanemab (promising phase 2 trial which technically failed but which showed a 64% Bayesian posterior probability of being at least 25% better than placebo) — that have shown a tendency to a roughly ~20-35% reduction in the pace of cognitive decline compared to placebo. That said, amyloid is very upstream in the causal chain, which begins about 15-20 years before clinically detectable symptoms. It's believed by some (including myself) that amyloid therapy would be preventative at that early stage, but you won't do much better than a ~35% slowdown at the stage Alzheimer's is typically diagnosed. At that stage, tau therapy is more promising, since it's the more proximate cause of neurodegeneration.

by tux3 5y ago

eightysixfour 5y ago

I only have a passing understanding, so forgive me if I get some of this wrong, but my understanding is that the beta amyloid hypothesis is "disproven" from the perspective that removing beta amyloid that has built up doesn't seem to resolve the symptoms. That is different than it isn't a causal link in the chain though. For example (making this up) I don't think we have disproven that beta amlyoid build-up causes inflammation, which actually causes the brain damage via a process that continues even once the beta amyloid is gone.

tux3 5y ago
What I find puzzling if the plaques are a link in the chain (as opposed to a symptom), isn't so much that beta-amyloid drugs stop short of outright resolving the symptoms, but that they don't seem to affect the progress of the disease. To continue with your example, if beta-amyloid was a major source of inflammation, and inflammation caused the damage, it'd seem reasonable to expect that removing the plaques would result in slowed cognitive decline. Strangely, this does not seem to happen in clinical trials.
randcraw 5y ago
As I recall, several studies have also shown that people can have high levels of amyloid-beta plaques (ABPs) in the brain and not show any signs of dementia. Between the two outcomes (ABPs exist but there's no decline, and ABPs are removed but dementia persists), the prevailing interpretation is that ABPs alone do not cause Alzheimer's. They seem to arise along with the cognitive loss, though not cause it. Tau deposits and associated neurofibrillary tangles have also been implicated in dementia, but also can be absent in those with the disease, so they too are not directly causal.
- catlikesshrimp 5y ago
  Everything you said is still consistent with the beta amyloid theory. The plaques don't cause dementia, they are supposed to lead to damage. Once dementia sets in, there is no turning back, the neuronal network has been damaged enough and you can't replace neurons (not most of them) Dementia is the main symptom of Alzheimer. And there are other causes of dementia, too.
- ABetaMale 5y ago
  The current most plausible perspective is amyloid-β pathology causes tau pathology which causes neurodegeneration. Thus it's not surprising that amyloid-β pathology can exist without neurodegeneration, if there is no tau pathology (or none yet). However, I have not heard of the opposite: people with cognitive decline and amyloid-β pathology but no tau pathology.

goda90 5y ago

Could it be that the amyloid-beta plaques are just a by-product of the same thing that is causing the damage in the first place?

ABetaMale 5y ago
That's a natural a priori hypothesis but there's extremely strong evidence that amyloid is causally upstream. For example, mutations in the enzymes or proteins involved in the production of amyloid-β (APP, PSEN1, and PSEN2), which structural analysis show have the direct effect of producing either more total amyloid-β, or more of amyloid-β 42 (the specific peptide implicated in Alzheimer's), deterministically cause Alzheimer's. That puts amyloid-β causally upstream at least in those cases, the so-called autosomal dominant variety, which are ~1% of Alzheimer's cases. The remaining ~99% of cases are less straightforward to interpret, but the disease looks essentially the same as the ~1% of cases described above: first amyloid-β builds up in the default mode network, then it spreads throughout the brain, eventually reaching the medial temporal region where primary age-related tauopathy (PART) is waiting, only then does the tau pathology spread, and neurodegeneration follows the tau pathology in lockstep. The way the amyloid-β and tau proteins misfold in autosomal dominant and sporadic Alzheimer's are the same, too, even though other tau pathologies have different tau folds. So basically, there's every reason to believe sporadic Alzheimer's is essentially the same disease as the one which we're basically certain is caused by amyloid-β.

monopoledance 5y ago

From what I got from skipping over the study, this isn't about beta-amyloid itself, but "triglyceride-rich lipoprotein" amyloid beta complexes. The amyloid beta plaques may be not cause, but symptom of the disease. Maybe the TRL-A-betas are causing the damage, get metabolized and after that the protein separates and then accumulates in the brain? The study states, the TRL-A-beta are causing inflammation, which they attribute for disease progression rather than A-beta plaque formation. > ...the findings presented in this study nonetheless support a now large body of evidence that demonstrates that the genesis of plaque is not the initiating trigger for neurodegenerative processes to be initiated, but rather, may be consequential. This study provides evidence that more subtle chronic interactive effects of peripheral metabolism of TRL-Aβ with the cerebrovasculature may be sufficient to potentially cause AD. So, clearing up A-betas may be just flushing the "damage logs".

ethbr0 5y ago
> This study provides, for the first time, direct evidence that hepatic expression of genes leading to the synthesis of human-Aβ is causally associated with corruption of the NVU, with cell death and brain atrophy realised. [...] Consistent with the hypothesis of increased neurovascular insult as a consequence of hepatic synthesis of TRL-Aβ, PET findings clearly demonstrated an age-associated increase in [Pittsburgh compound] uptake. We suggest that this was indicative of the marked abundance of amyloid-rich lipofuscin aggregates distributed within brain parenchyma and within vessel lumen. They definitely seem to lean into the neurovascular damage angle. I.e. liver produces amyloid-beta complexes, high levels of which result in neurovascular damage, resulting in lipids making it through and accreting in the brain. Which makes sense, as if your capillaries are less functional, how would you body clear plaques from a difficult to reach organ (the brain)?

lumost 5y ago

It's also possible that something which causes the liver to synthesize amyloids is the causative agent in alzheimers. In which case the amyloids may be a by-product.

ABetaMale 5y ago

Amyloid-targeting drugs have not failed. There are currently three — aducanumab (phase 2 trial successful, one of two phase 3 trials successful), donanemab (successful phase 2 trial), and lecanemab (promising phase 2 trial which technically failed but which showed a 64% Bayesian posterior probability of being at least 25% better than placebo) — that have shown a tendency to a roughly ~20-35% reduction in the pace of cognitive decline compared to placebo. That said, amyloid is very upstream in the causal chain, which begins about 15-20 years before clinically detectable symptoms. It's believed by some (including myself) that amyloid therapy would be preventative at that early stage, but you won't do much better than a ~35% slowdown at the stage Alzheimer's is typically diagnosed. At that stage, tau therapy is more promising, since it's the more proximate cause of neurodegeneration.