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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?

#271

Post by raverbashing »

rob_c wrote: post #263
raverbashing wrote: post #250

Earlier quoted context omitted.

> There are also money issues like with the alzheimer's situation. (that is: If climate change is dooming us then we should send more money to climate scientists) Absolutely, the issues are similar And if this can upend the business model of some big companies we'll give some "incentives" to some "doubtful" scientists even if their doubts are unfounded (actually very well founded but you get the gist) Which sucks bec…

> we should send more money to climate scientists. Couldn't disagree more. Please spend it on those who might actually fix something. There's plenty of can remove carbon or can undo the effect of X on Y. Let's stop falling back on the bad argument of we must leave nature alone right after arguing we change billion dollar industries because we can. We shouldn't learn to be custodians watching the planet die because of…

Actually my "Absolutely" referred to the first phrase, not the second one (my bad!)

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

#272

Post by trhway »

gruez wrote: post #242
trhway wrote: post #112

Earlier quoted context omitted.

there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality. wrt. original post - quickly googled, and that for example https://www.news-medical.net/health/What-are-Amyloid-Plaques... - pretty short and seems to be clear that amyloids do have some correlation while may or may be not the cause. "Amyloid plaques form one of the tw…

>there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality. Is that supposed to be an endorsement or a dismissal? The ostensible goals of "rationality" seem like good things, so it sounds like an endorsement, but in the wake of the FTX/SBF fallout they got a bad rap.

there is a big difference between a theory/idea and espousing the theory/idea as an ideology.

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

#273

Post by pcrh »

zosima wrote: post #266
pcrh wrote: post #264

Earlier quoted context omitted.

Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late. [0] https://www.cochrane.org/evidence/CD016297_are-medicines-ant...

That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never used outside clinical trials, with the new anti-amyloid antibodies, that does show modest efficacy in reducing the speed of progression. While these two classes of drugs target the same molecule, they are developed to target amyloid-beta in very different forms…

The point of systematic reviews is to be un-biased. So if their question is whether targeting Aβ amyloid is a valid approach they have to include the unsuccessful trails as well as those purported to be successful.

As to the trials specifically for Lecanemab and Donanemab, the benefits are not claimed to be either strong or large, even by those who support it. The current support these receive is more aligned with the concept that an improved targeting of Aβ amyloid might improve outcomes. This remains to be demonstrated.

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

#274

Post by btilly »

jhedwards wrote: post #193
bradley13 wrote: post #145

Earlier quoted context omitted.

Pretty clearly not. It would seem that beta amyloids correlate with Alzheimer's, but do not cause it. The problem us "consensus science". You could get funding to research beta amyloids, but not to research any competing hypotheses. It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.

> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic. I'm not sure I understand this. We've added hundreds of gigatons of carbon to the atmosphere. There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative:…

Yes, there is overwhelming evidence of climate change. And that we are causing it.

However research into what we humans can do to ameliorate it is verboten. For example https://www.scientificamerican.com/article/fertilizing-ocean... was an actual experiment that found a low cost way to both remove lots of CO2, and improve a fishery. But that line of research has been shut down.

Likewise research into the current impact is only allowed if it agrees with what is politically correct. For example many researchers have found that current severe California forest fires are mostly due to poor past policies, that have resulted in very dense forest, with a large fuel overload. But research that stresses the impact of climate change are easier to publish, and this shifts the apparent consensus on the causes of things like the major 2025 fires in the Los Angeles area.

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

#275

Post by btilly »

bradley13 wrote: post #145
gruez wrote: post #35

Earlier quoted context omitted.

> Problem was, the model was wrong. I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immediately incorrect. At best, it means its foundations are shakier than we thought, but it's not a slam dunk repudiation. [1] https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

Pretty clearly not. It would seem that beta amyloids correlate with Alzheimer's, but do not cause it. The problem us "consensus science". You could get funding to research beta amyloids, but not to research any competing hypotheses. It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.

The problem is that the top researchers in the field have spent their lives devoted to amyloid beta. They may well have helped direct hundreds of millions in grants to this line of research.

The idea that they have blocked the treatment of Alzheimer's rather than helping it, is very, very painful. This is perfect for creating cognitive dissonance.

And so, no matter what the evidence, they remain committed to the conclusion.

As a result, the latest Alzheimer's drug to enter stage 3 FDA trials is Trontinemab. (It is currently in stage 3.) It targets the amyloid target.

A relative drop in the bucket is going to, say, the infection hypothesis. This despite the fact that the only intervention that has been shown to reduce the incidence of Alzheimer's, is the shingles vaccine.

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

#276

Post by rustyhancock »

pcrh wrote: post #264
zosima wrote: post #252

The genetic evidence that amyloid-beta is in some way causative of at least a subset of Alzheimer's disease is still extremely strong. The fact that amyloid-beta binding drugs like Lecanemab and Donanemab decrease progression is also very strong evidence for the amyloid-beta hypothesis. What seemed to be the hurdle was likely, that targeting amyloid-beta in its pathological form just wasn't easy and developers of pha…

Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late. [0] https://www.cochrane.org/evidence/CD016297_are-medicines-ant...

Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies.

It's legimate as people with DS have a hugely increased risk of AD. Their risk increase seems likely related specifically to Amyloid. Many with DS can consent to it.

In general my completely gut feeling is that once we can target Tau we might find that targeting amyloid is needed to fully curtail progression.

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

#277

Post by pcrh »

rustyhancock wrote: post #276
pcrh wrote: post #264

Earlier quoted context omitted.

Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late. [0] https://www.cochrane.org/evidence/CD016297_are-medicines-ant...

Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies. It's legimate as people with DS have a hugely increased risk of AD. Their risk increase seems likely related specifically to Amyloid. Many with DS can consent to it. I…

Agreed, using these anti-amyloid treatments at an early stage in people with a high risk of early onset Alzheimer's disease, such as those with Down's syndrome, is likely the most robust test available of the theory that Aβ amyloid is directly causative of this disease.

Trials are currently ongoing. The results should start trickling out in a few years...

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

#278

Post by anon84873628 »

DANmode wrote: post #200
anon84873628 wrote: post #61

Earlier quoted context omitted.

Gee, that sure is a confident statement of fact. Or maybe virus activity is one way that a negative feedback loop involving protein aggregates can begin ...

“Complications due to unaddressed microbial infection” will read as pretty confident, too, but it’s still pretty vague once you’ve really dug in.

That's why I was emphasizing "one way" and "can begin".

Clearly viral infection may be a distal factor but it is not the proximate cause of Alzheimer's... which is quite conclusively due to protein aggregates.

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

#279

Post by picsao »

jhedwards wrote: post #193
bradley13 wrote: post #145

Earlier quoted context omitted.

Pretty clearly not. It would seem that beta amyloids correlate with Alzheimer's, but do not cause it. The problem us "consensus science". You could get funding to research beta amyloids, but not to research any competing hypotheses. It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.

> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic. I'm not sure I understand this. We've added hundreds of gigatons of carbon to the atmosphere. There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative:…

[dead]

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

#280

Post by dtgriscom »

jleyank wrote: post #30

They had a biological model. They had multiple drugs that were showed activity against that model, and effectiveness in humans. Problem was, the model was wrong. Pharma’s burned billions chasing this as it’s possibly the biggest market imaginable. Whether it was fraudulent or just incorrect is a different question. We don’t know all of the details of human biology. We don’t even know what all we don’t know. Most gues…

> Edit: Google the in the pipeline blog. This and other have discussed this at length.

Derek Lowe's blog is excellent, with 192 posts tagged "Alzheimer's Disease":

https://www.science.org/topic/blog-category/alzheimers-disea...

And, on a more entertaining topic:

https://www.science.org/topic/blog-category/things-i-wont-wo...

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