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Why has there been so little progress on Alzheimer's disease?

freakonomics.com

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Re: Why has there been so little progress on Alzheimer's disease?

#341

Post by pfisherman »

pcrh wrote: post #322
zosima wrote: post #321

Earlier quoted context omitted.

I wonder. Because if that was the question, why would they include anti-amyloid treatments that were never approved and are not part of any current treatment regimen and dilute the real effect of the approved antibodies? (Not that the approved antibodies are a silver bullet, but clearly they have some positive effect.)

The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so wer…

No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.

Re: Why has there been so little progress on Alzheimer's disease?

#342

Post by pcrh »

pfisherman wrote: post #341
pcrh wrote: post #322

Earlier quoted context omitted.

The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so wer…

No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.

The first GLP-1 receptor agonist to enter clinical trials was exenatide by Amylin Pharmaceuticals. It worked from the get go.

Re: Why has there been so little progress on Alzheimer's disease?

#343

Post by pcrh »

zosima wrote: post #339
pcrh wrote: post #322

Earlier quoted context omitted.

The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so wer…

Yes, the new anti-amyloids are not a revolutionary therapy. But they do have a small but definite effect on disease-progression. (something which in a highly noisy indication like Alzheimer's may actually mean a lot more to the patients than it seems by looking at the data. E.g. donepezil and memantine have very modest effects too, but patients and caregivers are still surprisingly positive about them). And since the…

All the trials included in the Cochrane review demonstrated removal of Aβ amyloid from the brain. Side effects were relatively modest, except for edema and micro-bleeds. So they are all legitimate tests of the hypothesis that removing Aβ amyloid would be beneficial.

Re: Why has there been so little progress on Alzheimer's disease?

#344

Post by zosima »

pcrh wrote: post #342
pfisherman wrote: post #341

Earlier quoted context omitted.

No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.

The first GLP-1 receptor agonist to enter clinical trials was exenatide by Amylin Pharmaceuticals. It worked from the get go.

But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide.

Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body.

Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak effect on weight loss, would obviously be badly misleading.

Re: Why has there been so little progress on Alzheimer's disease?

#345

Post by pcrh »

zosima wrote: post #344
pcrh wrote: post #342

Earlier quoted context omitted.

The first GLP-1 receptor agonist to enter clinical trials was exenatide by Amylin Pharmaceuticals. It worked from the get go.

But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide. Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body. Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak…

If you grouped all GLP-1 agonists that had entered clinical trials, they would be shown as successful [0]. No GLP-1 receptor agonist has failed to reduce appetite in clinical trials, but some were better than others.

The point about the anti-amyloid trials is that they all succeeded in removing amyloid. But they did not improve cognition, and only some resulted in a slightly slower rate of decline in cognition (people still declined).

[0] https://pubmed.ncbi.nlm.nih.gov/39841962/

>Forty-seven RCTs were included, with a combined cohort of 23,244 patients. GLP-1 RAs demonstrated a mean weight reduction of -4.57 kg (95% CI -5.35 to -3.78), mean BMI reduction of -2.07 kg/m2 (95% CI -2.53 to -1.62), and mean waist circumference reduction of -4.55 cm (95% CI -5.72 to -3.38) compared with placebo.

Re: Why has there been so little progress on Alzheimer's disease?

#346

Post by idiotsecant »

tim333 wrote: post #328
idiotsecant wrote: post #308

Earlier quoted context omitted.

I am baffled by the number of people on HN, presumably a website for and by technical people, who fail to consider secondary and tertiary effects when it fits their worldview to do so. There is a yawning abyss of states in between extinction and 'boy sure is a few degrees warmer out here' and none of them are good. Many organisms would benefit from a warmer climate, just not humans. We rely on extremely narrow condit…

I get your point but on the other hand humans live quite well in places like Medicine Hat say where it swings from -40 C in winter to +40 C in summer. Against that the likely warming by say 2100 is I think 1.5C up from what it is today which might be just about noticeable?

Did you read the post at all? Second order effects, not primary effects. Its exasperating how much effort people will put into not understanding the smallest things when they are inconvenient to their worldview.

Re: Why has there been so little progress on Alzheimer's disease?

#347

Post by zosima »

pcrh wrote: post #345
zosima wrote: post #344

Earlier quoted context omitted.

But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide. Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body. Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak…

If you grouped all GLP-1 agonists that had entered clinical trials, they would be shown as successful [0]. No GLP-1 receptor agonist has failed to reduce appetite in clinical trials, but some were better than others. The point about the anti-amyloid trials is that they all succeeded in removing amyloid. But they did not improve cognition, and only some resulted in a slightly slower rate of decline in cognition (peopl…

This is ridiculous.

Your meta review has like 80%-90% of the studies on semaglutide and liraglutide. When finding random effect per drug, they even say this:

> Hence, the drugs eligible for meta-regression were semaglutide (subcutaneous injection, once weekly) and liraglutide (subcutaneous injection, once daily), which both showed a dose-dependent treatment effect in terms of weight and BMI.

And the class-effect is much more modest than semaglutide by itself would have shown, exactly as I said. What is the point?

Re: Why has there been so little progress on Alzheimer's disease?

#348

Post by pcrh »

zosima wrote: post #347
pcrh wrote: post #345

Earlier quoted context omitted.

If you grouped all GLP-1 agonists that had entered clinical trials, they would be shown as successful [0]. No GLP-1 receptor agonist has failed to reduce appetite in clinical trials, but some were better than others. The point about the anti-amyloid trials is that they all succeeded in removing amyloid. But they did not improve cognition, and only some resulted in a slightly slower rate of decline in cognition (peopl…

This is ridiculous. Your meta review has like 80%-90% of the studies on semaglutide and liraglutide. When finding random effect per drug, they even say this: > Hence, the drugs eligible for meta-regression were semaglutide (subcutaneous injection, once weekly) and liraglutide (subcutaneous injection, once daily), which both showed a dose-dependent treatment effect in terms of weight and BMI. And the class-effect is m…

Both meta-analyses above cover all eligible clinical trials for the respective strategies, targeting the GLP-1 receptor, or targeting amyloid.

For the GLP-1 strategy, Table 1 in the above paper shows that all drugs were clearly effective. Some were better than others.

For the amyloid strategy, only some of the drugs were effective, and that efficacy was very weak, even when all the drugs removed amyloid. This brings into question the hypothesis that removing amyloid would alleviate AD, i.e. the slender benefits of Lecanemab might not be caused by amyloid removal. The same cannot be said for the GLP-1 receptor agonists.

Re: Why has there been so little progress on Alzheimer's disease?

#349

Post by jvanderbot »

deepsun wrote: post #340
jvanderbot wrote: post #233

Earlier quoted context omitted.

That is not a tautology. But you're right it's trivially true.

> In logic and mathematics, it is a statement that is true in every possible interpretation or situation.

... by definition

Tautology day is today because today is tautology day.

... not by "obviousness"

I can't check every stone for moss. We can't know every detail about anything.

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