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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?

#251

Post by [deleted] »

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.

[deleted]

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

#252

Post by zosima »

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 pharmaceuticals instead focused (for unknown reasons) on the solid amyloid-beta grains in the brain.

The major reason things are moving so slowly is because of the long development times of pharmaceutical compounds. A new compound will at least have to spend 2-3 years in safety studies before being tested on its first real patient, and then for Alzheimer's, which is a slowly developing disorder, nothing short of a 2-year followup time will show efficacy unless it's truly a miracle compound.

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

#253

Post by tim333 »

slashdave wrote: post #236

One of the most important ingredients of a proposal for a drug development program is viability: is there a path to market. The issue with Alzheimer’s is that until recently there was no practical diagnostic test. Without a test, there is no way to run a clinical trial. No clinical trial means no drug approval. Research is halted before it even begins.

The effects of Alzheimer’s are pretty obvious. I don't think not being able to detect it is much of an issue.

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

#254

Post by snapetom »

mehrshad wrote: post #42

https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte... "Despite being described as a “cabal,” the amyloid camp was neither organized nor nefarious. Those who championed the amyloid hypothesis truly believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug. It has not worked out that way. Research focused on amyloid, and the developmen…

I was outraged when I first read that article, but taking a step back and catching up on recent progress, I came to the same conclusion you did. Words like "nefarious", "fraud", and "corrupt" were thrown around, but no one was actively was seeking to do harm.

The harm was done by the groupthink and the sucking up of resources to research alternative causes. One of the comments on HN when that statnews article was first linked was by a commenter who worked on Alzheimer's. They agreed and I remember the line, (something to the effect of) "if you wanted funding for alternative investigations, you had to still throw a bone to beta amyloid in your proposal."

Was it all a waste? No. Current thought is beta amyloid is still involved, but Alzheimer's is multicausal. What those other causes are is in its investigation infancy. We could have started investigating those decades ago if the scientific research complex were truly open to new ideas.

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

#256

Post by dnautics »

stingraycharles wrote: post #158
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 think this is not a great example, as there’s a huge group of people that, in fact, does not agree with the consensus and would happily fund research that (tries to) prove otherwise. I fully agree with your point, though, just not the example.

having worked in amyloid, and in an a-beta lab in the second half of the 2000s, we always said under our breath in group meetings that we were skeptical about the amyloid hypothesis, but our grant applications certainly did not say that (or if they did it was a quick throwaway sentence). And I think the lab that I landed in was one of the most honest scientific labs in biochemistry/chemical biology.

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

#257

Post by lawrenceyan »

I'd argue the reason we’ve spun our wheels on Alzheimer's for decades isn't just about a flawed amyloid model. It’s a symptom of a much larger, dying paradigm in biotech.

For decades, the industry standard was to hunt for targeted small molecules to solve singular biological issues. And to be fair, I don't think this was because of a lack of vision as it was simply the strict limit of our technological capabilities at the time. But attempting to treat a cascading, systemic disease like Alzheimer's with a single targeted molecule is like hoping replacing one pipe will solve the problem when the issue is that the entire plumbing system is corroding.

This fundamental mismatch is exactly why clinical progress has stalled, and I believe the future of treating Alzheimer's will instead closely mirror how our approach to oncology has evolved.

We spent years searching for a universal molecule to cure cancer before we accepted reality. We now know that effective treatment often requires sequencing a tumor's mutanome to develop a highly personalized intervention for the individual. As neurodegenerative systems fail with age, we face that exact same biological complexity. A traditional small molecule is not going to rescue a globally failing network.

My personal take is that we won't see a true breakthrough in Alzheimer's until capital fully rotates out of these legacy, single-target pipelines and into programmable biological systems.

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

#258

Post by D-Coder »

ifwinterco wrote: post #118
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…

Huge codebase with years of fixes, features and hacks added on top and nothing ever refactored. It’s a miracle it works at all

A billion years of kludges.

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

#259

Post by ramraj07 »

rcxdude wrote: post #241
ramraj07 wrote: post #209

Earlier quoted context omitted.

Im not gonna try to correct you because its probably going to be futile, but I implore you to paste this thread into chatgpt and ask where you could be wrong in your logic. Correlation not causation is all the more important in a topic like this; nothing you said suggests amyloid causes alzheimers or just forms because of it.

Just say your point instead of dancing around it.

What exactly do I need to say further? My first comment was that "scientists today still don't understand correlation =/= causation" and the replies are all scientists who try to explain again how correlation can still mean causation (no it doesn't, and it definitely doesn't in this case and that has been the root cause from the beginning). So I tried to implore you to go review your text yourself, but you are clearly above it, so not sure what else I could do here.

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

#260

Post by naveen99 »

SomaticPirate wrote: post #109
dvfjsdhgfv wrote: post #95

Earlier quoted context omitted.

I think you are wrong, for several reasons. From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole). From marketing and sales perspective, look at what happen to pharma companies capitalization when Ozempic appeared: a relatively small El…

I agree with you but Ozempic is a bad example here. Part of the reason it is so valuable is that patients usually must take it for the rest of their lives. Its actually the perfect example of “evil” pharma since patients slmost akways regain the weight if they stop taking it. This leads to dependence or people searching for grey market sources. An example of “good” pharma would be Hepatitis C. We can now cure that. A…

Average person in the world earns about $300k in a lifetime. So it’s hard to charge more than that per person.
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