[oaktrout]

From what I've read, those drugs are very good at removing amyloid, but despite that, they don't seem to make much of a noticeable (clinically meaningful) difference in the people treated with them. I personally would not call that a "huge success".

If they are so good at cleaning up the amyloid, why don't people have more of an improvement? I think everyone agrees amyloid is associated with Alzheimer's, the question is how much of a causative role does it play.

[DavidSJ]

From what I've read, those drugs are very good at removing amyloid, but despite that, they don't seem to make much of a noticeable (clinically meaningful) difference in the people treated with them. I personally would not call that a "huge success".

After many decades of research, we've gone in the last few years from no ability whatsoever to affect the underlying disease, to 30% slowdown. To be clear, that's a 30% slowdown in clinical, cognitive endpoints. Whether you call that "meaningful" is a bit subjective (I think most patients would consider another couple years of coherent thinking to be meaningful), and it has to be weighed against the costs and risks, and there's certainly much work to be done. But it's a huge start.

If they are so good at cleaning up the amyloid, why don't people have more of an improvement?

No one is expected to improve after neurodegeneration has occurred. The best we hope for is to prevent further damage. Amyloid is an initiating causal agent in the disease process, but the disease process includes other pathologies besides amyloid. So far, the amyloid therapies which very successfully engage their target have not yet been tested in the preclinical phase before the amyloid pathology initiates further, downstream disease processes. This is the most likely reason we've seen only ~30% clinical efficacy so far. I expect much more efficacy in the years to come as amyloid therapies are refined and tested at earlier phases. (I also think other targets are promising therapeutic targets; this isn't an argument against testing them.)

I think everyone agrees amyloid is associated with Alzheimer's, the question is how much of a causative role does it play.

To be clear, the evidence for the amyloid hypothesis is causal. The association between amyloid and Alzheimer's has been known since Alois Alzheimer discovered the disease in 1906. The causal evidence came in the 1990's, which is why the scientific community waited so long to adopt that hypothesis.

[YZF]

Reading between the lines if we gave people those drugs before they show any symptoms we should be able to do even better. Has this been tested? How safe are those drugs? What should the average person be doing to avoid accumulating amyloids in the first place?

[DavidSJ]

Reading between the lines if we gave people those drugs before they show any symptoms we should be able to do even better. Has this been tested?

I do expect early enough anti-amyloid treatment to essentially prevent the disease.

Prevention trials of lecanemab and donanemab (the two antibodies with the clearest proof of efficacy and FDA approval) are ongoing: https://clinicaltrials.gov/study/NCT06384573, https://clinicaltrials.gov/study/NCT04468659, https://clinicaltrials.gov/study/NCT05026866

They have not yet completed.

There were some earlier prevention failures with solanezumab and crenezumab, but these antibodies worked differently and never showed much success at any stage.

How safe are those drugs?

There are some real safety risks from brain bleeding and swelling, seemingly because the antibodies struggle to cross the blood-brain barrier, accumulating in blood vessels and inducing the immune system to attack amyloid deposits in those locations rather than the more harmful plaques in brain tissue. A new generation of antibodies including trontinemab appears likely to be both more effective and much safer, by crossing the BBB more easily.

What should the average person be doing to avoid accumulating amyloids in the first place?

There's not much proven here, and it probably depends on your individualized risk factors. There's some evidence that avoiding/properly treating microbial infection (particularly herpes viruses and P. gingivalis) can help, since amyloid beta seems to be an antimicrobial peptide which accumulates in response to infection. There may also be some benefit from managing cholesterol levels, as lipid processing dysfunction may contribute to increased difficulty of amyloid clearance. Getting good sleep, especially slow wave sleep, can also help reduce amyloid buildup.

[jamesblonde]

What about supplementation with curcumin?

[Earw0rm]

Would it be fair to say that it's causal in terms of process, but perhaps not in terms of initiation?

That is, there's a feedback loop involved (or, likely, a complex web of feedback processes), and if a drug can effectively suppress one of the steps, it will slow the whole juggernaut down to some extent?

Am reminded a little of the processes that happen during/after TBI - initial injury leads to brain swelling leads to more damage in a vicious cycle. In some patients, suppressing the swelling results in a much better outcome, but in others, the initial injury, visible or not, has done too much damage and initiated a failure cascade in which treating the swelling alone won't make any difference to the end result.

[DavidSJ]

I’m not sure I understand the process vs. initiation distinction you’re asking about, but yes I do believe there are other targets besides amyloid itself which make sense even if the amyloid hypothesis is true. Anything in the causal chain before or after amyloid but prior to neurodegeneration is a sensible target.

[Earw0rm]

Sure, I was just talking about a step in a feedback loop or degenerative spiral rather than whatever initiates the feedback loop in the first place.

[akoboldfrying]

>If they are so good at cleaning up the amyloid, why don't people have more of an improvement?

I have zero knowledge in this field, but there's a very plausible explanation that I think is best demonstrated by analogy:

If you shoot a bunch of bullets into a computer, and then remove the bullets, will the computer be good as new?

[nradov]

Have you seen the price of ammunition lately? I think we'll need a huge NIH grant to run that experiment.

[virginwidow]

... Had to wipe the screen.

THANK YOU

> a huge NIH grant

One sentence like a Simo Häyhä round.

NIH & grants are a result -- of what cause? Urgently I encourage curious minds to rigorously & objectively discover "what cause"

[michaelcampbell]

Does your computer exhibit any plasticity? After how long are we taking the post-sample?