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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?

#111

Post by StableAlkyne »

londons_explore wrote: post #101
cpgxiii wrote: post #67

Earlier quoted context omitted.

> The FDA's approval process is stymied by a CYA culture that fails to adopt the risk profile it needs to in order to potentially save large contingents of sick and dying. Except the history of FDA approval here is that it has been too accepting of drug candidates for Alzheimers with very weak evidence of efficacy and serious side effects. This particular field would probably be better off if the FDA took a harder po…

I would like to see the FDA get rid of their binary "Approved" approach. Instead, at the start of a treatment on a patient, an analysis must be done of all available data, and the treatment only allowed if the error bars put it within the realm of the best treatment available. That means at the start when not much data is available, it is easy to give it to a patient. But over time as more data comes in it gets harde…

The struggle is the high level regulatory bodies (with the exception of aberrations such as the current admin's approach to appointment) generally select for individuals with a low risk tolerance. Low risk tolerance is generally incompatible with speed - it's a miracle the covid vax and treatments were approved as quickly as they were in 2020.

Biggest example of this risk aversion is the peptide craze going on (the most famous of which are GLP-1 antagonists). It's pretty much a wild west where people read a low-sample animal study, and buy a drug that's "for research only, not for human consumption" off of a compounding pharmacy in China.

Few human studies because even if you have willing and enthusiastic volunteers it's too expensive and creates legal liability. And the FDA cannot approve it without a high bar of evidence (for effective treatment and low risk) and costly, time consuming reviews. Because of this, there is a black market for the things and people are basically being their own test subjects.

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

#112

Post by trhway »

Drupon wrote: post #108
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...

>I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field If anyone wants to know who wrote the article linked before wasting time reading it, there you go.

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 two defining features of Alzheimer’s disease, the other being neurofibrillary tangles"

Interesting that the latter is inside the neurons while the former is outside - speaking of complexity. The article also describes that activating microglia back helps with amyloid plaques while this

https://pubmed.ncbi.nlm.nih.gov/33010092/#:~:text=The%20stud...

"The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. "

Human body reminds a large monolith codebase - fixing one thing breaks some other :). Claude Code, Human Body CRISPR edition, can't come soon enough...

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

#113

Post by totierne2 »

Mistletoe wrote: post #107
mongol wrote: post #97

Earlier quoted context omitted.

Awful how?

My spreadsheet says it makes me feel incredibly sleepy.

I took lithium for it got to my kidneys never thought of more generally microdosing lithium. Interesting. Full dose yeah flat and sleepy. Not sure it was the reason for flat out brain rot. (Other factors were available maybe just getting older.) Full dose needs blood tests as overdose weirdly bad. From due to dehydration / holiday in the sun looked like almost drunk but not drinking slopy etc. Slightly clingy desparate for interaction with strangers. . Not informed of damage relative seemed to recover ok. .

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

#115

Post by moffkalast »

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…

> We don’t even know what all we don’t know.

Somewhat ironic given the context.

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

#118

Post by ifwinterco »

trhway wrote: post #112
Drupon wrote: post #108

Earlier quoted context omitted.

>I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field If anyone wants to know who wrote the article linked before wasting time reading it, there you go.

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

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

#119

Post by friendzis »

gruez wrote: post #35
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…

> 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...

It's a classic example of "correlation does not imply causation". It was indeed observed that some patients with neurodegenerative conditions do indeed have amyloid plaques. It was further observed that patients with known Alzheimer's do not necessarily have amyloid plaques and patients without it do have plaques. The existence of amyloid plaques itself or the level, apparently, correlates extremely poorly, if at all, with the existence, onset or severity of the disease. Drugs attacking amyloid plaques might work, but they don't reverse the disease and do very little to slow progression. That's all scientific observations.

> I thought despite the fraud, it's still the best model we have[1]?

It is observed that one of the features of neurodegenerative diseases is decline in glucose metabolism. Supplementing energy availability (e.g. ketones [1], creatine [2]) does improve symptoms in patients with wide variety of CNS diseases, including Alzheimer's, senile dementia, epilepsy, and migraines.

The ATN model you have linked might as well be just ONE OF possible pathways to glucose uptake inhibition, which could be the causal pathology of the symptoms.

So no, it is very much not necessarily the best model we have. Inhibiting any pathway towards a disease is always a good thing, but the characteristics of "best" models are broad applicability and we have a serious contender.

[1]: https://link.springer.com/article/10.1016/j.nurt.2008.05.004 [2]: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.100...

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

#120

Post by throwaway84849 »

hn_throwaway_99 wrote: post #90

I'm surprised there was no mention (at least none that I found when searching) of the relatively recent research coming out of Harvard regarding the hypothesis that low levels of lithium in the brain are responsible for a lot of Alzheimer's cases. The research is still in the very early stages (largely mouse models, though they did develop the hypothesis by looking at differences in human brain tissue post mortem), b…

Interesting. I'm also taking orotate, and like the other comment here, it makes me very sleepy (so I'm taking much less than 1mg/day). Maybe that's the brain working to "take out the trash?"

Earlier today I read a comment here mentioning Dr Michael Nehls who writes about lithium and also dementia (highly recommend his books). Now that comment is no longer there. Hmmm.

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