5 ms·

You can be interested in what you want. But the interest in anti-amyloid therapy came from the basic science indicating amyloid pathology as the critical but-fo

You can be interested in what you want. But the interest in anti-amyloid therapy came from the basic science indicating amyloid pathology as the critical but-for cause of the disease. It wasn't just a blind shot in the dark. To my knowledge, there's no such basic science behind a keto diet for Alzheimer's.

msandford 2y ago
Turns out there are enough studies for a meta analysis. Is that basic science? I'm not sure what counts. https://www.sciencedirect.com/science/article/pii/S1279770724003932 https://www.sciencedirect.com/science/article/pii/S127977072... If amyloid is truly the critical "but for" cause then how on earth is it possible that reducing amyloid burden doesn't really make a difference? https://scopeblog.stanford.edu/2024/03/13/why-alzheimers-plaque-attack-drugs-dont-work/ https://scopeblog.stanford.edu/2024/03/13/why-alzheimers-pla...
- DavidSJ 2y ago
  Turns out there are enough studies for a meta analysis. Is that basic science? Basic science in this context means research investigating the underlying disease process to develop knowledge of how it works mechanistically, as distinguished from (and as a precursor to) developing or testing treatments for the disease. This helps us direct resources in plausibly useful directions rather than merely taking shots in the dark, and it also helps us to interpret later clinical findings: e.g. if we see some cognitive benefit in a three-month trial, is that because the underlying disease process was affected (and hence the benefit might persist or even increase over time), or might it be because there was some symptomatic benefit via a completely separate mechanism but no expectation of a change in trajectory? For example, cholinergic drugs are known to provide symptomatic benefit in Alzheimer disease but not slow the underlying biological processes, so that worsening still continues at the same pace. Or if we see results that are statistically borderline, is it still worth pursuing or was the very slight benefit likely a fluke? So a meta-analysis of ketogenic diets in Alzheimer disease is not basic science, though that doesn't mean it's useless. But what I'm saying is it's really helpful to have a prior that the treatment you're developing is actually targeting a plausible disease pathway, and the amyloid hypothesis gives us that prior for amyloid antibodies in a way that, to my knowledge, we don't have for ketogenic diets. https://www.sciencedirect.com/science/article/pii/S127977072 https://www.sciencedirect.com/science/article/pii/S127977072... Thanks, I just took a look at this meta-analysis. The studies with the strongest benefits on the standard cognitive endpoints of MMSE and ADAS-Cog — Taylor 2018, Qing 2019, and Sakiko 2020 — all lasted only three months, which makes me suspect (especially given the context of no theoretical reason to expect this to work that I'm aware of) this is some temporary symptomatic benefit as with the cholinergic drugs I mentioned above. But it's enough of a hint that I'd support funding a long-term trial just to see what happens. If amyloid is truly the critical "but for" cause then how on earth is it possible that reducing amyloid burden doesn't really make a difference? I've argued elsewhere in the thread that it does make quite a difference, but there's still a lot of work to do, and I've said what I think that work is (mainly: improving BBB crossing and administering the drugs earlier).
  - msandford 2y ago
    There was absolutely no theoretical reason that some moldy cheese would kill bacteria but thankfully Fleming noticed what happened and we got antibiotics. There was no theoretical reason that washing your hands would do anything to combat the spread of disease and all the smart doctors knew otherwise. Some kooky doctor named Semmelweisz proposed that doctors should wash their hands between childbirths in 1847, 14 years before Pasteur published his findings on germ theory in 1861. When some doctors listened to him maternal mortality dropped from 18% to 2%. I'm all for basic science when the statistical significance becomes so great it really starts to look like causality and then you start figuring stuff out. It doesn't seem like the statistical significance of the amyloid theory is strong enough that the direction of the arrow of causality can be determined. That's too bad. The strength of the effect of keto diet interventions in Alzheimer's is pretty strong to my understanding. Which should be aggressively hinting that there's likely some as-yet unknown causality that's worth investigating. We don't have to spend billions to do that. But we do need more funding for it which is hard to get while all the amyloid hypothesis folks are really invested and clamoring.
    - DavidSJ 2y ago
      There was absolutely no theoretical reason that some moldy cheese would kill bacteria but thankfully Fleming noticed what happened and we got antibiotics. Again, I'm in favor of people investigating all sorts of random shit. I agree that sometimes unexpected things pan out. If you want to run a carefully conducted, large long-term trial on ketogenic diets in Alzheimer's, I support you. I'm just skeptical it'll pan out, and on priors I'll put greater expectation on the approach with a scientifically demonstrated mechanistic theory behind it. I'm all for basic science when the statistical significance becomes so great it really starts to look like causality and then you start figuring stuff out. It doesn't seem like the statistical significance of the amyloid theory is strong enough that the direction of the arrow of causality can be determined. What are you basing this one? The p-value on lecanemab's single phase 3 trial was below 0.0001. And the causal role (not mere association) of amyloid in the disease has been demonstrated for years before significant efforts were invested developing therapies to target amyloid in the first place; most convincingly in the genetic mutations in APP, PSEN1, and PSEN2.
vixen99 2y ago
It's possible you might adopt a different attitude if one day you're diagnosed with rapid onset Altzheimer. At that stage you'd be forgiven for muttering 'basic science be blowed'. Keto (or whatever) offered some relief for my friend Bill, I'll give it a try given it's my survival at stake. Plate tectonics was suggested in 1913 and not supported (to put it politely) at that point by 'basic science'. It took until 1960 to be accepted. A paradigm shift was needed as Kuhn explained. Meanwhile, this paper (2024) https://www.sciencedirect.com/science/article/pii/S1279770724003932 https://www.sciencedirect.com/science/article/pii/S127977072... 'Effects of ketogenic diet on cognitive function of patients with Alzheimer's disease: a systematic review and meta-analysis' concludes "Research conducted has indicated that the KD can enhance the mental state and cognitive function of those with AD, albeit potentially leading to an elevation in blood lipid levels. In summary, the good intervention effect and safety of KD are worthy of promotion and application in clinical treatment of AD."

msandford 2y ago

Turns out there are enough studies for a meta analysis. Is that basic science? I'm not sure what counts. https://www.sciencedirect.com/science/article/pii/S1279770724003932 https://www.sciencedirect.com/science/article/pii/S127977072... If amyloid is truly the critical "but for" cause then how on earth is it possible that reducing amyloid burden doesn't really make a difference? https://scopeblog.stanford.edu/2024/03/13/why-alzheimers-plaque-attack-drugs-dont-work/ https://scopeblog.stanford.edu/2024/03/13/why-alzheimers-pla...

DavidSJ 2y ago
Turns out there are enough studies for a meta analysis. Is that basic science? Basic science in this context means research investigating the underlying disease process to develop knowledge of how it works mechanistically, as distinguished from (and as a precursor to) developing or testing treatments for the disease. This helps us direct resources in plausibly useful directions rather than merely taking shots in the dark, and it also helps us to interpret later clinical findings: e.g. if we see some cognitive benefit in a three-month trial, is that because the underlying disease process was affected (and hence the benefit might persist or even increase over time), or might it be because there was some symptomatic benefit via a completely separate mechanism but no expectation of a change in trajectory? For example, cholinergic drugs are known to provide symptomatic benefit in Alzheimer disease but not slow the underlying biological processes, so that worsening still continues at the same pace. Or if we see results that are statistically borderline, is it still worth pursuing or was the very slight benefit likely a fluke? So a meta-analysis of ketogenic diets in Alzheimer disease is not basic science, though that doesn't mean it's useless. But what I'm saying is it's really helpful to have a prior that the treatment you're developing is actually targeting a plausible disease pathway, and the amyloid hypothesis gives us that prior for amyloid antibodies in a way that, to my knowledge, we don't have for ketogenic diets. https://www.sciencedirect.com/science/article/pii/S127977072 https://www.sciencedirect.com/science/article/pii/S127977072... Thanks, I just took a look at this meta-analysis. The studies with the strongest benefits on the standard cognitive endpoints of MMSE and ADAS-Cog — Taylor 2018, Qing 2019, and Sakiko 2020 — all lasted only three months, which makes me suspect (especially given the context of no theoretical reason to expect this to work that I'm aware of) this is some temporary symptomatic benefit as with the cholinergic drugs I mentioned above. But it's enough of a hint that I'd support funding a long-term trial just to see what happens. If amyloid is truly the critical "but for" cause then how on earth is it possible that reducing amyloid burden doesn't really make a difference? I've argued elsewhere in the thread that it does make quite a difference, but there's still a lot of work to do, and I've said what I think that work is (mainly: improving BBB crossing and administering the drugs earlier).
- msandford 2y ago
  There was absolutely no theoretical reason that some moldy cheese would kill bacteria but thankfully Fleming noticed what happened and we got antibiotics. There was no theoretical reason that washing your hands would do anything to combat the spread of disease and all the smart doctors knew otherwise. Some kooky doctor named Semmelweisz proposed that doctors should wash their hands between childbirths in 1847, 14 years before Pasteur published his findings on germ theory in 1861. When some doctors listened to him maternal mortality dropped from 18% to 2%. I'm all for basic science when the statistical significance becomes so great it really starts to look like causality and then you start figuring stuff out. It doesn't seem like the statistical significance of the amyloid theory is strong enough that the direction of the arrow of causality can be determined. That's too bad. The strength of the effect of keto diet interventions in Alzheimer's is pretty strong to my understanding. Which should be aggressively hinting that there's likely some as-yet unknown causality that's worth investigating. We don't have to spend billions to do that. But we do need more funding for it which is hard to get while all the amyloid hypothesis folks are really invested and clamoring.
  - DavidSJ 2y ago
    There was absolutely no theoretical reason that some moldy cheese would kill bacteria but thankfully Fleming noticed what happened and we got antibiotics. Again, I'm in favor of people investigating all sorts of random shit. I agree that sometimes unexpected things pan out. If you want to run a carefully conducted, large long-term trial on ketogenic diets in Alzheimer's, I support you. I'm just skeptical it'll pan out, and on priors I'll put greater expectation on the approach with a scientifically demonstrated mechanistic theory behind it. I'm all for basic science when the statistical significance becomes so great it really starts to look like causality and then you start figuring stuff out. It doesn't seem like the statistical significance of the amyloid theory is strong enough that the direction of the arrow of causality can be determined. What are you basing this one? The p-value on lecanemab's single phase 3 trial was below 0.0001. And the causal role (not mere association) of amyloid in the disease has been demonstrated for years before significant efforts were invested developing therapies to target amyloid in the first place; most convincingly in the genetic mutations in APP, PSEN1, and PSEN2.

vixen99 2y ago

It's possible you might adopt a different attitude if one day you're diagnosed with rapid onset Altzheimer. At that stage you'd be forgiven for muttering 'basic science be blowed'. Keto (or whatever) offered some relief for my friend Bill, I'll give it a try given it's my survival at stake. Plate tectonics was suggested in 1913 and not supported (to put it politely) at that point by 'basic science'. It took until 1960 to be accepted. A paradigm shift was needed as Kuhn explained. Meanwhile, this paper (2024) https://www.sciencedirect.com/science/article/pii/S1279770724003932 https://www.sciencedirect.com/science/article/pii/S127977072... 'Effects of ketogenic diet on cognitive function of patients with Alzheimer's disease: a systematic review and meta-analysis' concludes "Research conducted has indicated that the KD can enhance the mental state and cognitive function of those with AD, albeit potentially leading to an elevation in blood lipid levels. In summary, the good intervention effect and safety of KD are worthy of promotion and application in clinical treatment of AD."