4 ms·

Billions have been spent because it's a challenging disease to understand and treat. I want big progress too. But we shouldn't let our desire for big progress c

Billions have been spent because it's a challenging disease to understand and treat. I want big progress too. But we shouldn't let our desire for big progress cause us to lose our ability to objectively evaluate evidence. I have no opposition to a properly controlled randomized controlled trial of the keto diet, or other proposed therapies (many of which have been conducted, and are for targets other than amyloid which are completely compatible with the amyloid hypothesis). Until a proper RCT of keto is conducted, anecdotal claims are worth very little compared to the evidence I referred to.

stefantalpalaru 2y ago
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msandford 2y ago
I'm far, far more interested in anecdotes about completely halting or reversing decline than I am in rock solid data about a 30% reduction in decline speed. Antibiotics started out as an anecdote about something whose effect was so stark it couldn't be missed. Chasing promising anecdotes is far more valuable (in my opinion) than attempting to take a 30% effect to a 100% effect. Others are free to feel differently of course. I'm open to hearing about 100 different times that finding a tiny effect that got grown and magnified into a huge effect that totally changed medicine. I'm just not aware of many at this point.
- DavidSJ 2y ago
  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).
  - 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."

stefantalpalaru 2y ago

[dead]

msandford 2y ago

I'm far, far more interested in anecdotes about completely halting or reversing decline than I am in rock solid data about a 30% reduction in decline speed. Antibiotics started out as an anecdote about something whose effect was so stark it couldn't be missed. Chasing promising anecdotes is far more valuable (in my opinion) than attempting to take a 30% effect to a 100% effect. Others are free to feel differently of course. I'm open to hearing about 100 different times that finding a tiny effect that got grown and magnified into a huge effect that totally changed medicine. I'm just not aware of many at this point.

DavidSJ 2y ago
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).
- 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."