Hacker News Board Hacker News, browsed like a classic message board
Live data from Hacker News

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

monash.edu

Post reply on HN
Print view View original

91–100 of 150 posts

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

#91

Post by AussieWog93 »

cassepipe wrote: post #23
quadhome wrote: post #5

Alzheimer’s is driven by the buildup of toxic proteins called amyloid-beta. In the words of Derek Lowe: Amyloid-directed therapies truly, truly do not appear to be the answer for Alzheimer’s treatment. When I started work in the field back in the early 1990s, I was convinced of the opposite - the evidence looked very strong that defects in amyloid processing were indeed the cause of the disease. But that was thirty-f…

This is just one person's (informed I assume) opinion tough. It does sound like common sense but alas common sense is rarely a good guide when it comes down to how the body works. I don't have a dog in this fight and I don't remember that much but I read someone's "in defense of the amyloid hypothesis" with interest. So if you want an counterpoint, you can go read https://www.astralcodexten.com/p/in-defense-of-the-am…

Somewhat tangential, but when I was doing my PhD there was a bizarre amount of research thrown into testing ML algorithm after ML algorithm at bad EEG data in the hope that we'd be able to magically find a signal from noisy garbage input data.

"Progress" consisted of someone finding a new algorithm that just so happened to get good performance on one particular dataset (but not others).

Everyone knew it was bullshit but did it anyway, because it was easy to convince people to give you grants if you have a sexy, sellable hypothesis and a willingness to handwave away the two decades of prior non-progress.

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

#92

Post by armadsen »

avgDev wrote: post #68
dbcurtis wrote: post #14

Earlier quoted context omitted.

> Alzheimer’s is driven by the buildup of toxic proteins called amyloid-beta. Isn't the current thinking that amyloid-beta buildup is a marker, not a cause? The therapy may be working here, but it isn't clear whether clearing amyloid-beta proteins is the mechanism or an outcome.

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 may actually be the cause and 2. you start treating it early, years before symptoms start, disease onset may be significantly delayed. There’s no way to know right now except to try it of course.

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

#93

Post by armadsen »

nphardon wrote: post #46
avgDev wrote: post #19

My mother has early onset alzheimer's disease. We currently know very little about the disease and the current treatment options are controversial. The efficacy of the medications removing the amyloid plaque from the brain is questionable, as people still decline. What makes alzheimer's difficult is that it is not really a single uniform disease. There are subtypes. Since my mother has it, I was presented with an opt…

How old is your mother? Iirc PSEN1 correlates to very early AD, like late 30s early 40s. My dad had full blown AD at 65, with serious cognitive decline starting at 63, and that felt very early to us all. My dad had no AD biomarkers on full genetic scan. My heart goes out to you and your family.

There are multiple specific possible mutations that cause 100% penetrant dominantly inherited early onset Alzheimer’s. And there are three genes where mutations can cause it: PSEN1, PSEN2, and APP. The average age of onset seems to depend on the specific mutation. In my (wife’s) family, onset is mid 40s to mid 50s. Some families get it even earlier, but 30s seems rare.

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

#94

Post by armadsen »

avgDev wrote: post #19

My mother has early onset alzheimer's disease. We currently know very little about the disease and the current treatment options are controversial. The efficacy of the medications removing the amyloid plaque from the brain is questionable, as people still decline. What makes alzheimer's difficult is that it is not really a single uniform disease. There are subtypes. Since my mother has it, I was presented with an opt…

It’s sometimes frustrating to try to explain that the gene mutation in the family (PSEN1 in our case) means it’s a 100% chance you get it. Most people have never heard of it, so you get a lot of “well, maybe you’ll be lucky and it won’t affect you!” from well meaning people.

I’m very sorry for what you’re going through with your mom. My father in law had it and died a year ago at age 64 after 16 years of decline. Watching a truly brilliant person slowly lose their faculties and abilities until they don’t recognize their own family is awful.

Two of his kids have the mutation (not my wife, thankfully) and so we all hope that better treatments are available for them.

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

#95

Post by pama »

DavidSJ wrote: post #79
xenadu02 wrote: post #72

Earlier quoted context omitted.

Let's put all of that aside for a moment. When the first drugs targeting HIV arrived the results were undeniable. Yes the drugs sucked for various reasons and yes HIV would evolve resistance. But the data demonstrated a very clear link that these drugs suppressed HIV and suppressing HIV made people live longer. Or consider mRNA and COVID, a great success story where the technology was put to good use and the results…

Now if we consider amyloid beta therapies: we have treatments that target amyloid beta with varying degrees of success but at least some show definite reductions in amyloid beta plaques. To the best of my knowledge that has not shown to improve outcomes in Alzheimer's patients to any meaningful degree. This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed…

I work in drug discovery. For the past twenty years or so, my personal analogy for this hypothesis has been a fantasy story around the days after the bombing of Dresden, when a new civilization suddenly visits Dresden and has no priors about what may have happened there. The aliens see bricks all over the place and assume that the bricks were the cause of the catastrophe. They take great efforts to pick up the bricks and save a couple of lives from the people who were covered in the ruble. The aliens build better systems to pick up bricks in the future and get ready to act next time. When a nearby city gets bombed, they quickly visit and help recover bricks saving a couple more lives. A different civilization could have instead focused on reducing the bombs or detecting and defending against the attacking airplanes.

Our immune systems are complicated, much more so than airplanes and bombs. The amyloid deposits are very likely part of an immune response, and although in principle immune responses going wild are horrible and can be fixed, it is very important to work on identifying and addressing the causal factors of this disease. There have been more therapies tested on the amyloid hypothesis that mere statistical fluctuations could explain away. I don't always agree with Derek, but I'm with him on this one. New ideas are urgently needed here, or this horrible disease will be an increasingly common end state for our aging populations.

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

#96

Post by reinitctxoffset »

cassepipe wrote: post #23
quadhome wrote: post #5

Alzheimer’s is driven by the buildup of toxic proteins called amyloid-beta. In the words of Derek Lowe: Amyloid-directed therapies truly, truly do not appear to be the answer for Alzheimer’s treatment. When I started work in the field back in the early 1990s, I was convinced of the opposite - the evidence looked very strong that defects in amyloid processing were indeed the cause of the disease. But that was thirty-f…

This is just one person's (informed I assume) opinion tough. It does sound like common sense but alas common sense is rarely a good guide when it comes down to how the body works. I don't have a dog in this fight and I don't remember that much but I read someone's "in defense of the amyloid hypothesis" with interest. So if you want an counterpoint, you can go read https://www.astralcodexten.com/p/in-defense-of-the-am…

Derek Lowe is an extremely well-known and widely respected expert in the field of pharmaceutical drug discovery chemistry.

His series "In The Pipeline" has a cult following of experts and non-experts alike.

He is widely regarded as an authority on the chemistry of Alzheimer's.

For a fun introduction to his work, the "first hit is free" dopamine rush is his "Things I Won't Work With", a masterclass in bringing chemistry to life through the lens of synthesis actively dangerous to person and property.

You'll be up all night.

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

#98

Post by DavidSJ »

pama wrote: post #95
DavidSJ wrote: post #79

Earlier quoted context omitted.

Now if we consider amyloid beta therapies: we have treatments that target amyloid beta with varying degrees of success but at least some show definite reductions in amyloid beta plaques. To the best of my knowledge that has not shown to improve outcomes in Alzheimer's patients to any meaningful degree. This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed…

I work in drug discovery. For the past twenty years or so, my personal analogy for this hypothesis has been a fantasy story around the days after the bombing of Dresden, when a new civilization suddenly visits Dresden and has no priors about what may have happened there. The aliens see bricks all over the place and assume that the bricks were the cause of the catastrophe. They take great efforts to pick up the bricks…

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 genetic causal evidence emerged, which is why the amyloid hypothesis emerged at that time. Other important causal evidence has emerged since, especially that tau pathology (the proximate cause of neurodegeneration) is causally downstream of amyloid pathology, which we know from many lines of evidence now. (See the article for a lot more detail on all this, if you are curious.)

As for the possibility that the successes of amyloid therapies might be explicable by chance, this is highly implausible. Only three (aducanumab, lecanemab, and donanemab) of a dozen or more amyloid therapies successfully cleared plaque, and it is precisely those three that achieved a slowdown of cognitive decline in phase 3 trials (with aducanumab succeeding in only one of its two, but with the others succeeding in their only phase 3), several of which with p-values below 0.001. This is not p-hacking or reporting bias.

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

#99

Post by ohbleek »

MarkusQ wrote: post #50
cassepipe wrote: post #23

Earlier quoted context omitted.

This is just one person's (informed I assume) opinion tough. It does sound like common sense but alas common sense is rarely a good guide when it comes down to how the body works. I don't have a dog in this fight and I don't remember that much but I read someone's "in defense of the amyloid hypothesis" with interest. So if you want an counterpoint, you can go read https://www.astralcodexten.com/p/in-defense-of-the-am…

> Alzheimer’s isn’t my field, but I got very interested in it, spent six months studying the literature, and came away believing the amyloid hypothesis was basically completely solid. If the accusation is "the field has been captured by a group with a vested interest in a model based on fraudulent research, strongly biasing what gets funded and what gets published" I wouldn't expect "studying the literature" to be pa…

Thank you for writing out this reply, so I didn't have to. I think that somebody who is not working in medicine or pharma at all would not be able to understand how views have shifted concerning the amyloid-plaque theory. It is largely discussed as a theory that has been tested extensively and has only highlighted our lack of understanding of Alzheimer pathophysiology.

That last part isn't a sidenote, it's the entire reason for discussing the theory.

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

#100

Post by [deleted] »

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.

[deleted]
Post reply on HN