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.
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).
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.
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.
I agree more science is certainly better than less. But patentable therapies will always get a disproportionate amount of funding for big science (versus a basically-free dietary change).
There are certainly theoretical reasons why it might help. There is definitely a link between AD and blood sugar. Having diabetes doubles your risk of AD. The brain regions hit first and worst in AD have the highest levels of aerobic glycolysis (in which cells take glucose only through glycolysis and not oxidative phosphorylation, despite the presence of adequate oxygen).
To the extent a keto diet can reduce resting blood sugar levels and improve insulin sensitivity, there is good reason to think it is a candidate to slow AD.
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...
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).