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Copper transport drug restores memory and clears toxic Alzheimer's proteins

monash.edu

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Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#121

Post by thechao »

DavidSJ wrote: post #111
kurthr wrote: post #103

Earlier quoted context omitted.

Not only have I read it, I know people mentioned in it. There aren't very many.

You read the article in which I discuss the matter you say I was unfamiliar with?

I'm responding to a random comment: I was in molecular biology, but >20 years ago. Your article immediately presents as someone who's acquired reading expertise in a biological/medical subfield. Second, your initial survey presents as a "brittle x": AB is the proximal cause all by itself; but, it can also be the secondary cause from many vectors. Diseases like that are (essentially) impossible to explain to the public. Also, the biological principle function is a standard trope for "good for X in the short run, bad for the person in the long run".

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#122

Post by DavidSJ »

thechao wrote: post #121
DavidSJ wrote: post #111

Earlier quoted context omitted.

You read the article in which I discuss the matter you say I was unfamiliar with?

I'm responding to a random comment: I was in molecular biology, but >20 years ago. Your article immediately presents as someone who's acquired reading expertise in a biological/medical subfield. Second, your initial survey presents as a "brittle x": AB is the proximal cause all by itself; but, it can also be the secondary cause from many vectors. Diseases like that are (essentially) impossible to explain to the publi…

Thanks for these comments! The multiple pathways into a common entrypoint is definitely a challenge to communicate.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#123

Post by ncr100 »

DavidSJ wrote: post #78
kurthr wrote: post #75

Earlier quoted context omitted.

Wow, it sure didn't take long to show a complete lack of familiarity in the field. It seems like that's going to be a real weakness with LLMs based on volumes of material that are later discovered to be semi-fraudulent and unmotivated by scientific principals. https://stanforddaily.com/2023/12/31/blockbuster-alzheimers-...

As noted elsewhere in this thread, which you seem not to have read, I discuss that matter in the article, which you also seem not to have read.

This form of hostile challenge is discouraged in the HN rules:

https://news.ycombinator.com/newsguidelines.html

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#124

Post by pcrh »

DavidSJ wrote: post #56
dekhn wrote: post #54

Earlier quoted context omitted.

No, he's not (I work in pharma at a company that does basic and applied research on Alz). It's more correct to say there are several camps, but the camp promoting amyloid plaques as the causative/driver for Alz has struggled greatly to come up with evidence supporting its position.

Is your view that amyloid is actually a minority view among researchers? That seems completely wrong based on basically every conference proceeding I've viewed and the volume of papers and citations I've examined. If your view is merely that there is a "camp" of experts that disagrees, then sure, but in that case, I do not think it is honest to frame this as a choice between believing in the authority of a single exp…

I have direct experience of research into Alzheimer's disease, including specifically surrounding the amyloid cascade hypothesis.

The strength of the amyloid hypothesis is that it is currently the only way to unify early onset AD that is caused by mutations in APP and presenilin with the pathology of both early and late set AD.

The weakness is that experimental mice expressing mutated APP do not get neurodegeneration, despite showing amyloid accumulation and behavioral defects.

Mice expressing mutated presenilin in contrast do get both behavioral defects and neurodegeneration, despite showing no accumulation of amyloid.

"Perhaps mice are different" is the usual response/excuse.

This defense is considerably weaker now, given the very modest benefits of removing amyloid from the human brain, as shown in recent clinical trials.

So.... when considered rigorously, the amyloid hypothesis remains to be proven.

However, it will always have its supporters until there is an alternate explation for the convergence of mutations in APP and presenilin on precisely that region of APP that generates amyloid.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#125

Post by novia »

DavidSJ wrote: post #69
dekhn wrote: post #64

Earlier quoted context omitted.

My estimate of the quality of the evidence is based on daily discussions with people who work in that field and reading summary articles in major journals. I typically don't read raw scientific articles directly- those are aimed at people in the field. Instead, my understanding comes from a synthesis of expert opinions weighted by my own priors (based on 30+ years in the field). Derek's opinion is now the prevailing…

What started as an argument to ignore arguments and evidence and instead rely on authority, seems now to have morphed into an argument that we should ignore the authority of the establishment, because of your own personal assessment of the evidence (which you have not yourself read) and your own personal synthesis of conversations you've had with researchers you've personally come into contact with (despite this bein…

update your priors dude

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#126

Post by dekhn »

uxhacker wrote: post #114
dekhn wrote: post #64

Earlier quoted context omitted.

My estimate of the quality of the evidence is based on daily discussions with people who work in that field and reading summary articles in major journals. I typically don't read raw scientific articles directly- those are aimed at people in the field. Instead, my understanding comes from a synthesis of expert opinions weighted by my own priors (based on 30+ years in the field). Derek's opinion is now the prevailing…

Your making an argumentum ad verecundiam which even if you are right means we have to discredit it. It’s poor science to make an argument on authority, if you know the science then you should be quoting the published research and not relying on others so called expertise.

That's the dream (all science communication should be based in the raw scientific data as published in the literature) but it's not how things work now, nor is it even practical. Instead, we rely on experts (authorities) because our priors tell us that experts are usually the most able to interpret the complexity of literature.

One thing that has gone mostly unsaid in this thread is that scientists lie when they publish. Not every scientist, and not every publication, but significant fraction of papers contain true errors or omissions intentionally added by the paper authors. Learning how to read a paper and translate the bullshit takes some time, and usually requires a fairly deep understanding of the state of the art of the field.

I don't think you're obliged to discredit any argument made from authority (we're not making true logical arguments here, we're working in a real world space with ambiguouity).

Then the next question becomes 'which expert to trust'? which is a subjective judgement; personally, after polling many different experts, the "go look for other causes of alzheimer's" experts seemed to have the most compelling biological narrative.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#127

Post by avgDev »

armadsen wrote: post #92
avgDev wrote: post #68

Earlier quoted context omitted.

From what I read your statement is accurate. From speaking to people who are going through the new infusions Leqembi and Kisunla get rid of amyloid plaque doesn't mean the decline stops, and if the disease was driven by it then it would stop. Also, studies show some slowing using these new drugs, but the disease still progresses. Therefore, the plaque is most likely a symptom. It could be the driver in some of the ca…

My wife’s family has PSEN1-mutation EAD (my wife didn’t inherit it). In that particular case it does seem that the mutated genes relate directly to Amyloid production and clearing, and there are ongoing clinical trials for the use of the new monoclonal antibody drugs in treating it. Two of my family members are in a trial for Remternetug, specifically. There is hope that in that specific case where 1. Amyloid buildup…

Are you family members experiencing any symptoms of the disease?

I guess if my mother has the gene I will test for PSEN1 at some point, but I am worried about the side effects of the meds. Hope things go well for your family.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#128

Post by FatherOfCurses »

plomme wrote: post #115
dekhn wrote: post #34

Earlier quoted context omitted.

If I had to choose between Derek Lowe (author of the anti-amyloid-research article who is also highly experienced and skilled in pharma) and Scott Alexander/David Schneider-Joseph (psychiatrist and AI engineer, respectively), all my priors suggest Lowe gives better advice. "I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field, but I got very in…

I don't know anything about alzheimers but I'd hope someone that does would engage with David SJ's points instead of dismissing him on lack of authority alone.

Oh FFS what does any knowledge matter any more if we can now say that someone who has no medical training has the ability to turn the entire field of Alzheimers on its head?

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#129

Post by DavidSJ »

pcrh wrote: post #124
DavidSJ wrote: post #56

Earlier quoted context omitted.

Is your view that amyloid is actually a minority view among researchers? That seems completely wrong based on basically every conference proceeding I've viewed and the volume of papers and citations I've examined. If your view is merely that there is a "camp" of experts that disagrees, then sure, but in that case, I do not think it is honest to frame this as a choice between believing in the authority of a single exp…

I have direct experience of research into Alzheimer's disease, including specifically surrounding the amyloid cascade hypothesis. The strength of the amyloid hypothesis is that it is currently the only way to unify early onset AD that is caused by mutations in APP and presenilin with the pathology of both early and late set AD. The weakness is that experimental mice expressing mutated APP do not get neurodegeneration…

Those are amyloid-only mice. It's an amyloid+tau disease, with tau the proximate cause of neurodegeneration. Normal mice don't get tau pathology, whereas even healthy human beings do, however it stays localized until the presence of widespread amyloid pathology.

Causal intervention on amyloid+tau mice is consistent with causal mediation from longitudinal human neuroimaging data: the amyloid pathology greatly accelerates tau pathology, and then this causes neurodegeneration.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#130

Post by DavidSJ »

pama wrote: post #117
DavidSJ wrote: post #98

Earlier quoted context omitted.

The hypothesis that amyloid is simply a downstream effect, not a cause, is of course worth considering, and where my mind was at when I first approached the literature skeptically. The widespread presence of amyloid-beta plaques in Alzheimer's disease has been known since 1906, but the field didn't adopt the amyloid hypothesis for decades precisely because of this possibility. But then in the early 1990's, strong gen…

Regarding lack of p-hacking. The placebo arm of blinded trials breaks when your brain can detect a medication. The effect is tiny in these studies; approval was rushed to give hope to patients. The drug was discontinued later.

The drug was discontinued later.

You're thinking of aducanumab. Lecanemab and donanemab have been in widespread use for several years now, and open-label extensions vs. external controls showing increasing benefits over longer treatment durations.

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