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

Posted by bookofjoe 1 day ago

Comments

Comment by quadhome 1 day ago

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-five years ago, thirty-five years in which therapy after therapy after therapy aimed at amyloid mechanisms has failed.

[…] We’re way past persistence, way past focus, way past optimism and multiple shots on goal and old-college-tries. Do something else! For God's sake, do something else.

— https://www.science.org/content/blog-post/anti-amyloid-antib...

Comment by cassepipe 1 day ago

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-amyloid-h...

Comment by dekhn 1 day ago

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 interested in it, spent six months studying the literature, and came away believing the amyloid hypothesis was basically completely solid. I thought I’d share that understanding with current skeptics."

6 months of reading literature when you don't know how to read biomedical literature isn't very confidence inducing. I know this site really likes it when smart outsiders come in and disrupt the status quo, but... probably not in this case.

Comment by DavidSJ 1 day ago

This frequently comes up as a critique of my article, but I don't claim to be disrupting the field as a smart outsider. Rather, I looked at the field and concluded that the experts seem to know what they're doing. Derek Lowe is very much in the minority on this matter.

Comment by dekhn 1 day ago

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.

Comment by DavidSJ 1 day ago

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 expert from that camp, vs. the (lack of) authority of me, a non-expert.

(I also think your read of the evidence is wrong, but I won't restate the arguments in my article.)

Comment by dekhn 1 day ago

My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature (the entire amyloid establishment isn't going to give up its dominant position easily).

Also, I didn't say anything about the evidence (I don't have a "read" on the evidence, because I don't read Alz literature). My point is entirely that my priors indicate that Derek is a more reliable reader than you.

Comment by john_strinlai 1 day ago

>My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature

>I don't have a "read" on the evidence, because I don't read Alz literature

these two sentences seem contradictory to me. i am not sure how you would keep up on the research (to know it's moved from majority-held to minority-held view), and know that the move is not reflected in the literature, without reading the literature.

Comment by dekhn 1 day ago

Most scientists who are not experts in their field don't read the literature for a field directly. Instead, they synthesize their opinions about the field by consulting experts, and weighing various sorts of evidence. In my case, I work in an adjacent field and see presentations from scientists, have casual conversations with them, and read the news articles in major journals.

The raw literature for alzheimer's, as well as biomed in general, is not really easily interpretable. It's rife with errors, misleading statements, and intentional obfuscation.

Comment by DavidSJ 1 day ago

You said the camp promoting the amyloid hypothesis has struggled greatly to come up with evidence to support its position. What did you mean by that if not a read of the quality of the evidence?

Why do you continue to frame this as a choice between a single cherry-picked expert's opinion, and my own non-expert opinion? Either fairly represent the spectrum of experts' views, or decide based on the actual evidence and arguments.

Comment by dekhn 1 day ago

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 one that I hear from a wide range of researchers.

I've seen this happen before, btw- overturning establishment paradigms, especially ones where the underlying etiology is complex- is extremely hard and often takes decades of experimental results.

Comment by DavidSJ 1 day ago

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 being apparently unrepresentative of objective measures of typical researcher opinions).

Arguing from authority really only takes you so far when it ends up as an appeal to your personal experience. I'd rather you either address the arguments directly, or drop the dubious appeal to authority.

Comment by lmeyerov 1 day ago

I don't have a horse in this race, but for anyone who has worked in it, "science advances one funeral at a time" comes to mind here

Comment by novia 20 hours ago

update your priors dude

Comment by DavidSJ 18 hours ago

I did. I started out very skeptical, then got convinced by the quality of the evidence.

Comment by djdjkddkkd 1 day ago

[dead]

Comment by uxhacker 1 day ago

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.

Comment by dekhn 19 hours ago

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.

Comment by echelon 1 day ago

The amyloid and tau people have had over thirty years with nothing to show for it.

It's time for the inflammation / diabetes / infection / metabolic dysfunction / liver dysfunction folks to get more money to test their theories.

Comment by kurthr 1 day ago

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-...

Comment by DavidSJ 1 day ago

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.

Comment by ncr100 22 hours ago

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

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

Comment by DavidSJ 19 hours ago

That's fair. I responded to hostility with hostility. Perhaps I should have ignored the comment or just responded kindly despite the hostility.

Comment by kurthr 1 day ago

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

Comment by DavidSJ 1 day ago

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

Comment by thechao 1 day ago

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".

Comment by DavidSJ 23 hours ago

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

Comment by 1 day ago

Comment by pcrh 20 hours ago

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.

Comment by DavidSJ 19 hours ago

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.

Comment by pcrh 17 hours ago

I appreciate your comment. However, a straight-forward test of the hypothesis that amyloid is the toxic (etiological) agent in AD fails when tested in mice.

One may then ask, what is being remedied in the many, many, studies that claim to successfully target amyloid toxicity in mice? And is this relevant to the processes that occur in AD?

Human pathology studies are limited in ability to determine causal agents because they are primarily observational, i.e. they find correlations, show that changes in certain other proteins or processes are associated, such as tau that you mention, inflammation, etc. Or as you mention, show that the pathological hallmarks of AD have a stereotypical order of appearance.

However, the only human studies that can demonstrate cause in AD are genetic studies.

Comment by DavidSJ 16 hours ago

Thanks, great challenges.

One may then ask, what is being remedied in the many, many, studies that claim to successfully target amyloid toxicity in mice? And is this relevant to the processes that occur in AD?

I don't think studies rescuing cognitive deficits in amyloid-only mice are convincing evidence for the amyloid hypothesis, precisely because we know amyloid is not the proximate cause of neurodegeneration in actual Alzheimer's disease, and that proximate cause does not exist in those mice.

In other words, these mice are not faithful recapitulations of the full disease. They have their amyloid production turned up so far that their amyloid pathology seems to cause cognitive deficits, but that's not what's happening in humans. They are, at best, a good vehicle for testing specific narrow hypotheses about amyloid production and clearance. The field has largely moved on from amyloid-only mice as a direct predictor of clinical efficacy, and that was the right call.

Here is some data in living humans, besides genetics, that has relevance to causation, in my opinion:

- The location and severity of amyloid pathology is a poor spatiotemporal match to the sites of neuronal volume loss, and to the severity and nature of clinical deficits. However, the location and severity of tau pathology is a very good match to both of these things. Of course, since these observations are correlational in nature, they don't absolutely prove a specific causal theory. But they do rule out, for example, the idea that amyloid is proximately connected (by which I mean nearby somewhere in the causal graph) to the process of neurodegeneration, whereas tau seems to be very proximately connected. From this observation alone tau could be downstream or sidestream rather than upstream, but it does then suggest that whatever causes tau pathology is itself upstream of neurodegeneration, since correlations always have a cause (the correct statement that "correlation ≠ causation" simply means "correlation between A and B does not imply that A causes B", but the explanation must be either A causes B, B causes A, or C causes both A and B).

- Anti-amyloid antibodies which remove plaque in humans cause downstream reductions in tau pathology in humans, and, separately, have clinical benefits in those humans.

- The spatiotemporal progression of amyloid and tau pathology is highly consistent with the hypothesis that amyloid pathology greatly worsens the tau pathology, but not vice versa. And there's not an alternative explanation I've come across for this fact than that amyloid pathology worsens tau pathology.

All of the above facts are generally true in combined amyloid+tau mouse models as well as in vitro human cell studies, which is some reason to believe these are closer to faithfully recapitulating the disease than the amyloid-only models. Once we believe that, we can then do more causal interventions on those models which we couldn't do in humans, and learn more about causality. For example, we know that intentionally worsening amyloid pathology in amyloid+tau mouse models also causes tau pathology and neurodegeneration to worsen in mouse models. And because these models look closer to the full disease than the amyloid-only models, this is at least relevant causal evidence, though we always have to be open to the possibility that the disease models are still missing some important elements.

I'm not aware of an alternative hypothesis to the (ATN) amyloid → tau → neurodegeneration model which synthesizes all of the above facts, along with the genetic evidence for amyloid's causal role which you referred to. By contrast, I'm not aware of any evidence inconsistent with the ATN model.

Comment by pcrh 15 hours ago

Yes, there is a clear sequence of how AD pathology develops, starting with amyloidopathy and progressing to tauopathy, but 1) there is as yet no established molecular connection between the two, and 2) one should not conflate pathology with disease mechanisms.

So, taking the amyloid hypothesis itself (putting presenilin aside for the time being).

We know that mutations in APP do cause AD. How? And if amyloid is not the "proximate" cause of AD, how do mutations in APP cause AD? Include in this Down syndrome, where >90% of cases develop early onset AD by age 50. They have an extra copy of APP that is not mutated.

Furthermore, people can accumulate large amounts of amyloid in the brain without having any notable dementia.

Adding tau to the equation does not help much in explaining how APP mutations cause AD. All people have tau. Furthermore, mutations in tau do not cause AD, they cause different neurodegenerative diseases (e.g. frontotemporal dementia).

Combining APP mutations with presenilin mutation and/or tau mutations in mice does lead to worse outcomes, but the same could be said for combining any other random set of neurodegeneration-associated gene mutations.

Comment by DavidSJ 15 hours ago

Yes, there is a clear sequence of how AD pathology develops, starting with amyloidopathy and progressing to tauopathy, but 1) there is as yet no established molecular connection between the two, and 2) one should not conflate pathology with disease mechanisms.

I agree that the specific molecular mechanism(s) is/are currently unknown. I've seen a number of proposals, but to my knowledge there isn't smoking-gun evidence for any one of them. But there can be causal evidence that A causes B (such as which I list) which exceeds a mere sequence of "A first, then B", and without knowing the specific mechanisms by which A causes B.

A bit confused by these questions, and I suspect the confusion may have to do with the term "proximate". By "amyloid is not the proximate cause of neurodegeneration", I simply mean it is upstream, mediated by another cause (namely tau). I think that clarification answers these questions.

Furthermore, people can accumulate large amounts of amyloid in the brain without having any notable dementia.

As predicted by the ATN model, at least for some time. But there is a threshold of amyloid pathology that does seem to guarantee progression to tau pathology and dementia.

Sure, there are different tauopathies, each with a characteristic fold. All people have tau, but there's a specific AD tau fold emerging apparently from the locus coeruleus, then spreading to the hippocampus and entorhinal cortex, and it's this that seems heavily accelerated by the presence of amyloid pathology in humans. (By the way, a notable fact is that autosomal-dominant AD -- clearly caused by APP/PSEN1/PSEN2 mutations affecting amyloid production -- has the same tau fold as sporadic AD, even though the large majority of other tauopathies do not.)

Note I didn't just say it "leads to worse outcomes". It's specifically that amyloid pathology worsens tau pathology, and then neurodegeneration occurs colocated with the tau pathology. This cannot be said for other random sets of mutations, in general.

(By the way, basically all of these points are discussed in the article I wrote which got linked above. You're under no obligation to read it but it might save us some time.)

Comment by pcrh 14 hours ago

These points still don't explain how mutations in APP cause AD.

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. (One can ignore claims that this mutation increases Abeta oligomers, since the evidence is that Abeta oligomers are found at far too low concentrations in the human brain. They would have to be more toxic than ricin if they were etiological for AD). The oligomers seen on gels are an artefact, see the controversy surrounding Tessier-Lavigne).

As you state, and I agree, APP is upstream of tau in natural AD pathogenesis, but does not cause neurodegeneration in mice. So we still don't know from direct experimentation how APP leads to tauopathy and neuodegeneration. The evidence that this is through Abeta per se is tentative at best.

[0] A Second Pedigree with Amyloid-less Familial Alzheimer’s Disease Harboring an Identical Mutation in the Amyloid Precursor Protein Gene (E693delta) https://pubmed.ncbi.nlm.nih.gov/25743013/

Comment by DavidSJ 14 hours ago

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0].

This is interestingly similar to the Arctic Mutation, and in the same codon no less: no plaque, but still autosomal-dominant AD due to an APP mutation. I had previously taken the Arctic Mutation to be evidence that it's not plaque per se, put more likely protofibrils (which are components of plaques in normal AD, and still present under the Arctic Mutation) or precursor aggregates which are pathogenic. The fact that the Osaka Mutation blocks protofibril formation underlines the uncertainty, that you and I agree exists, on the detailed molecular mechanisms. I would be inclined to point then to oligomers, but you say the oligomers are found at far too low concentrations to be relevant — what's your source for this?

Not only APP, but also PS1+PS2 mutations of course, can cause ADAD, and the relevant mutations all seem to cause more Abeta42 production. In the sporadic case, production usually seems unchanged, but clearance is usually impaired (especially with ApoE4). What they all seem to have in common is amyloid production or clearance. I'm curious if you know of another pathway they have in common besides this. Otherwise it's hard to see what the alternative hypothesis is, which could explain the etiology of seemingly highly-similar disease trajectories (ADAD + sporadic AD).

I’ll add as an addendum: APP mutations do cause neurodegeneration in mice, if those mice are combined amyloid+tau models. This seems most faithful to the human disease.

Comment by pcrh 2 hours ago

No APP-alone mouse gets neurodegeneration resembling that seen in the human AD brain, i.e. with so-called "neuritic" plaques, tauopathy, spongiopathy and widespread neuronal death.

This is why researchers now most often use the 5XFAD mouse, which has APP with three mutations, and presenilin with two mutations (hence 5 FAD mutations) [0]. Note however that mutated presenilin alone is enough to cause neurodegeneration in mice, such mice however do not accumulate amyloid, which is why mutated APP in added to make the pathology more "realistic".

As to Aβ42, there are mutations in APP which cause familial AD, but produce exclusively Aβ40, e.g. APP A673V [1]. Note also that most studies report alterations in the ratio of Aβ42 to Aβ40, precisely because effects on the levels of Aβ production are inconsistent across APP mutations.

Nevertheless..... and despite my obvious skepticism towards the amyloid toxicity hypothesis, the mutations in APP that cause AD all cluster in or near the region of the protein that is Aβ. There must be a reason for that. It is also in contrast to presenilin, where the mutations are distributed throughout the molecule, indication a loss of presenilin function causes AD.

One alternate explanation to Aβ or oligomer toxicity is proposed toxicity of the immediate precursor to Aβ, i.e. the APP C-terminal fragment (CTF), see for example the recent paper below and references therein [2].

[0] https://www.alzforum.org/research-models/5xfad-b6sjl

[1] A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis https://pmc.ncbi.nlm.nih.gov/articles/PMC2728497/

[2] APP β-CTF triggers cell-autonomous synaptic toxicity independent of Aβ https://pmc.ncbi.nlm.nih.gov/articles/PMC12017768/

Comment by dekhn 13 hours ago

At this point you should just go to grad school in a molecular neurology program. You clearly have the passion for this sort of research, and it would probably be useful to immerse yourself in the process to get more experience and judgement. Grad programs in bio usually have journal clubs; bring one of your papers, and see what people think of it.

Comment by xenadu02 1 day ago

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 are obvious.

On the flip side we have certain cancers like certain breast cancers, melanoma, etc that never had a "wow" moment where some miracle turned them from highly fatal into treatable but we have seen decade after decade treatments improve and survival rates march ever upward such that what were once almost guaranteed death sentences are now often very treatable.

These are two disease treatment models worth keeping in mind. Sometimes major leaps are made. Sometimes progress is slow.

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.

That concerns me and I think justifies some skepticism of the amyloid hypothesis. The data is messy but if amyloid beta were a symptom not a cause that could certainly fit the results we are seeing. That doesn't mean the amyloid beta hypothesis is wrong but I think skepticism of the "state of the art" in the field is warranted given the pathetically ineffective progress made to date.

Comment by DavidSJ 1 day ago

This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article.

Comment by pama 1 day ago

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.

Comment by DavidSJ 1 day ago

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.

Comment by pama 1 day ago

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.

Comment by DavidSJ 19 hours ago

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.

Comment by stinkbeetle 1 day ago

Would you expect progression to cease if not reverse if the cause was cleared?

Comment by DavidSJ 1 day ago

Not reverse; the neurons have died.

Cease, yes, if the cause is removed early enough. But if you intervene too late (once symptoms are detectable), then the downstream tau pathology, which is what directly kills neurons, likely spreads on its own via a prion-like mechanism.

So far, no clinical trial has completed prior to clinical onset for an antibody which actually removes plaque. This is probably the main reason only 30% slowdown has been achieved so far. The donanemab prevention trial is due to complete next year. That will be an important one to watch.

Comment by laughing_man 1 day ago

Amyloid plaques could be part of a disease cascade. Not the root cause, in other words, but an additional downstream problem than probably still needs to be addressed.

Comment by DaveZale 1 day ago

Yes, and the fact that something like oral hygiene can influence AD would support your thesis. Often an infection in the gums/teeth can result in boils or worse in distant parts of the body. Add a dysfunctional blood brain barrier and you are screwed.

Brush and floss bruddahs.

Comment by xenadu02 16 hours ago

> This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article.

Perhaps I am just not well-informed but 30% slowdown in progression translates to sufferers have some mild improvement in cognitive tests and live a few months longer.

Maybe it is simply too early to tell but I would naively expect something much more significant. Perhaps this is the sort of thing that requires much earlier treatment to demonstrate better results.

I'm not saying amyloid beta research should be terminated. Merely that everyone in the field should be willing to entertain other ideas.

Comment by DavidSJ 12 hours ago

Perhaps I am just not well-informed but 30% slowdown in progression translates to sufferers have some mild improvement in cognitive tests and live a few months longer.

A few years longer. It's obviously frustratingly far from where we'd like to be. It was only a direct response to the claim that Alzheimer treatment isn't even in the "sometimes progress is slow" category, but rather in the "no meaningful benefit at all" category.

I'm not saying amyloid beta research should be terminated. Merely that everyone in the field should be willing to entertain other ideas.

We agree that people should be willing to entertain other ideas! I don't think anyone is saying otherwise.

Comment by FatherOfCurses 18 hours ago

But without any training in experimental methodologies, molecular biology, protein mechanics, pharmacology, or any of the other specialized fields that make up the world of Alzheimer's research, how do you view yourself as qualified to make that conclusion? What body of knowledge are you drawing on to conclude that the experts' reasoning is sound, they are properly controlling their experiments, they are drawing the correct conclusions based on the underlying mechanics? AFAIK even people who do meta-analyses are qualified in the field they are doing the analysis for.

Comment by DavidSJ 17 hours ago

This is a reasonable challenge. I won't and shouldn't be able to convince you that my process was satisfactory, but I'll describe it anyways.

I agree that I don't have the qualifications to check whether, for example, a particular cryo-EM study was conducted properly. But I can check whether those who do have such qualifications disagree on the methodology or findings of that particular study. There's a lively debate within the Alzheimer's research community; it's not hard to find dissenting opinions on just about anything, and I actively seek them out, and when such disagreement exists, I avoid weighting any evidence too heavily, unless the disagreement is about broader matters of synthesis or specific statistical or methodological questions in which my non-biological scientific background permits me to reach my own conclusions.

I am also careful not to heavily weight a single assumption-laden preclinical study conducted by a single lab, for example, but instead to look for "smoking gun"-style evidence, in those few cases that it exists, or to look at the bulk of evidence across many studies from many labs, where the specific conclusions do not seem to be seriously in doubt by experts. In general, I've been skeptical, considering alternative explanations wherever it seemed crucial to the bigger picture, and avoiding trusting anything that seemed like it involved knowledge which was heavily in the weeds on stuff that I couldn't understand. I had a personal motivation to understand the genuine truth here, and enough scientific background that I usually know when I'm out of my depth on a specific matter.

I think it's reasonable of you to say: that all sounds well and good, but I just don't know your process well enough to trust it, and you don't have formal qualifications on the matter, so I'll ignore what you say. I certainly wouldn't expect you to take anything on my authority. I see my article essentially as an act of science journalism, and scientific journalists often lack formal training in the field they report on. You can read it and see if the reasoning makes sense and the evidence is convincing, or you can reasonably ignore it and fall back on expert opinions.

I did the investigation precisely because the majority expert viewpoint was being called into question by a lot of non-experts, and I had a personal motivation to find out, genuinely, whether this critique was warranted. If you don't have that motivation, then it's probably not worth your time to do the same. I did, and I came away satisfied.

Comment by righthand 1 day ago

“Derek Lowe is very much in the minority”

Is putting your thumb on the scale against Lowe. When a few replies down from here some commenters have provided an article demonstrating the exact fraudulent science in favor of what Lowe is saying.[0] It seems you may very well be disrupting it because he has a minority opinion. So you’ve possibly spent 6 months understanding an incorrect and fraud supported thesis. That seems like an outsider trying to disrupt it by using their “Google/SpaceX” creds to claim authority on the work of insiders.

[0] https://news.ycombinator.com/item?id=48544407

Comment by DavidSJ 1 day ago

1. I don't say Derek Lowe is wrong because he's in the minority. Minorities are sometimes right. But since the parent comment was arguing on authority and my lack thereof, I point out only that one shouldn't cherry-pick one's choice of authorities. Either accept the majority opinion of the experts, or come to your own opinion based on the quality of the arguments and evidence.

2. I would never want anyone to believe what I say because of "Google/SpaceX creds" (I didn't even write that line, Scott added it, and only to provide a brief biography and acknowledge that I do not work in the field, not to lend an air of authority to my words).

3. There's no need to cite the fraud to me, since I already discuss it in my article. You are welcome to read that article and form your own opinion about the arguments therein.

Comment by cassepipe 1 day ago

Fair enough but it's not by Scott Alexander but a guest post by David Schneider-Jospeh

EDIT: They edited their message to reflect that

Comment by plomme 1 day ago

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.

Comment by FatherOfCurses 19 hours ago

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?

Comment by selimthegrim 1 day ago

This really has become the new physics now, right where they think they can invade any given field in six months because that’s how long it’s supposed to take physicists to learn AI

Comment by dekhn 1 day ago

In some ways physics is different from biology and medicine, I do think outsiders to physics can pick up and contribute a bit more easily (although it depends on field). Biomed just has an absolute insane amount of ambiguous knowledge that mostly gets picked up through diffusion across decades of learning. And many of the results in the literature are just wrong (one of the reasons I stopped being a researcher was seeing just how bad the publication record in biology is).

BTW, many physics people pick up the mechanical bits of machine learning/AI very quickly since they have all the foundational mathematics. The harder parts are understanding all the methods/tricks/complexity that got us to the state of the art- similar to biomed, you just sort of have to immerse yourself amongst knowledgeable people and let their knowledge diffuse in.

Comment by palmotea 1 day ago

> 6 months of reading literature when you don't know how to read biomedical literature isn't very confidence inducing.

Come on, he's a software engineer, a little reading will give him a shit-ton of confidence.

Comment by himata4113 1 day ago

Makes me wonder if this is the typical correlation != causation argument where amyloids are produced and are simply a marker/symptom rather than the cause.

Comment by bigbuppo 1 day ago

I'm pretty sure there's an xkcd for this.

Comment by MarkusQ 1 day ago

> 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 particularly helpful in assessing the claim. It's sort of like saying "I read all of Enron's press releases and SEC filings, and they sound legit."

The defense reads more like a special pleading or sunk cost fallacy. There has been a lot of research done on one hypothesis, actively excluding alternatives, so that hypothesis deserves to be considered until disproven (he does, iirc, allow for a test that would de-privilege the amaloyd hypothesis).

Comment by ohbleek 1 day ago

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.

Comment by AussieWog93 1 day ago

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.

Comment by giantg2 1 day ago

If I remember the studies right, removing the plaque doesn't reverse the dementia, and some drugs that show improvements in the dementia don't remove the plaque. There's clearly other stuff going on.

Comment by fnordpiglet 1 day ago

No actually there’s a large body of quashed research over these decades that went against the prevailing hypothesis. It’s one of the key examples of how peer review fails to consider novel approaches in the face of consensus even if consensus is shown to likely be wrong. The fact the original research driving the consensus was fraudulent at worst made it that much more sad.

To be clear this isn’t about whether it’s right or wrong it’s about that science involves investigating all avenues with evidence, proof, and rigor. Group think is how we end up incorporating bias into science, which is anti scientific.

Comment by cassepipe 1 day ago

I believe you don't have read the link I posted because its author does address the narrative you present here

But again I am not saying you are wrong and I am even sympathetic to this narrative but ultimately, unconvinced, either way

Comment by uxhacker 1 day ago

Groupthink is very much the scientific method. According to Imre Lakatos the key question is does the group expand knowledge or contract it (very rushed reply as about to catch a flight)

Comment by biomcgary 1 day ago

In Lakatosian terms, the amyloid hypothesis is an example of a degenerating research program that has largely failed to predict new observations and is primarily driven by post hoc reasoning. The hypothesis was rescued by research claiming a significant new observation that was ultimately shown to be fraudulent (https://pmc.ncbi.nlm.nih.gov/articles/PMC12397490/).

From a Lakatosian perspective, the amyloid hypothesis is not necessarily wrong, but it is not paying off in terms of empirical insights relative to the amount of attention and funding it has received.

Comment by jjtheblunt 1 day ago

Proofs and Refutations is a great book

https://a.co/d/0cXTgHgv

Comment by a_conservative 1 day ago

An example of fraud in research that contributed to the consensus.

> The 2006 paper suggested an amyloid beta (Aβ) protein called Aβ*56 could cause Alzheimer’s.

https://www.science.org/content/article/researchers-plan-ret...

Comment by reinitctxoffset 1 day ago

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.

Comment by klibertp 17 hours ago

He's the guy from FOOF[1]! I didn't immediately make the connection, thanks. Yeah, that series was kind of fun, even if it kind of reinforced my layman understanding that all chemists are explosion nerds :D

[1] https://www.science.org/content/blog-post/things-i-won-t-wor...

Comment by dbcurtis 1 day ago

> 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.

Comment by chermi 1 day ago

Yes. And to anyone paying attention, this has been current since about 2010.

Comment by whatisthiseven 1 day ago

I remember reading about this then and I am no where near the biomedical field.

I almost couldn't believe we are still talking about the same causes of alzheimers 16 years later.

Comment by avgDev 1 day ago

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 cases though, I think in genetic PSEN1 alzheimer's. I've read a paper discussing issue with the body not removing it and allowing to build up.

Comment by armadsen 1 day ago

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.

Comment by avgDev 19 hours ago

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.

Comment by armadsen 8 hours ago

My father in law passed away from it about a year and a half ago at age 64. Two of his kids have tested positive for the mutation. They don’t have symptoms yet (they’re in their 20s and 30s).

Comment by bijowo1676 1 day ago

I read it somewhere that amyloid plaques were actually defensive mechanism of the body to counter the damage to brain from disease, so removing the plagues makes things worse for patients

https://www.salk.edu/news-release/in-surprising-twist-some-a...

Comment by 1 day ago

Comment by bluGill 1 day ago

I care what works, not about debate. This seems to work and that trumps any debate about what the real means are.

Don't get me wrong, if you are in this area of research this debate is important. There may be other types of Alzheimer's that have a different means. This drug may actually target something else. There might be some other truth I haven't thought it - but to me as an outsider the important part is a treatment that works, not why it works.

Comment by TaupeRanger 1 day ago

You are wrong. This paper very clearly does not show that it "works". The debate exists for a good reason - the very thing this paper claims to show is the exact thing the person you replied to was questioning. And that is a central question in all of Alzheimer's research.

There are dozens of studies that show mice improving their memory/spatial reasoning as Alzheimer's models. None of them have led to a proven improvement in longevity or quality of life for human Alzheimer's patients. Some of them slightly slow the progression, but even then you're getting into a gray area - is it really "better" to be stuck in the Alzheimer's fog for longer? Are we actually improving quality of life? It's unclear.

So no, in order for us to say that this approach "works", we would need randomized controlled clinical trials in humans showing a strict improvement in quality of life and/or longevity. This is not even close to that level of evidence.

Comment by dgoldstein0 1 day ago

> Over 56 days, the treatment reduced toxic amyloid-beta by 42 per cent and improved spatial learning by nearly 44 per cent

So there's some benefit. Sounds like their next step is a much larger trial to answer the question you are posing.

Comment by mimicmagnet 1 day ago

https://pubs.acs.org/doi/10.1021/acschemneuro.6c00252

In mice. This is a repeating trend in Alzheimer's research, where the amyloid-beta treatment works in the mouse model but not on humans, because the mouse model induces the amyloid-beta issue (mice don't really get Alzheimer's) and then we treat it.

Comment by bluGill 1 day ago

It is a repeating trend in all medical research. However enough does turn out to work in humans that we eventually make useful progress.

Comment by wk_end 1 day ago

In general, sure, but in this specific instance (treating Alzheimer's by clearing amyloid-beta) it's been shown over and over again to not work in humans.

Comment by russfink 1 day ago

I’m kinda new to this - so what you’re saying is the mouse model induces beta-amyliods directly, rather than finding ways to give mice Alzheimer’s, whereas the human tests are for humans that have Alzheimer’s? Meaning we aren’t doing any tests of simply stimulating BA growth in humans?

Comment by wk_end 1 day ago

I'm also not exactly on expert on this myself, take it with a grain of salt, but my understanding is that we don't really know what Alzheimer's is. To our knowledge there isn't a clear physical cause we can point to - a virus or bacteria or tumor or something. We have the symptoms, and we have the observation that Alzheimer's patients have amyloid plaques in their brain - among other differences!

Since mice don't ever get Alzheimer's naturally, and we don't actually know what Alzheimer's is, we don't know what it would even mean to give mice Alzheimer's. But for research we've genetically engineered mice that end up with lots of those plaques, and their behaviour does suggest an impairment similar to Alzheimer's, so that's what we've been working with. And in those models, various treatments that involve clearing the plaques does seem to help resolve that impairment - but they don't help humans with Alzheimer's, even if they do clear the plaques there too.

If I'm reading your question correctly, we can't stimulate amyloid plaque growth in humans for experimentation because that'd almost certainly be considered completely unethical. And also our methods for inducing the amyloid plaques involve mice that are genetically modified from birth rather than something we introduce in vivo, which would somehow be even more unethical than experimenting on live humans. It's possible we could make those genetic modifications in vivo now with recent developments in gene therapy, but...why?

Comment by XorNot 1 day ago

Which is not the point of the research paper: the point of it is they've targeted a novel mechanism (waste clearing) and observed two effects impacting markers for Alzheimer's.

Amyloid beta might not be causative, but if you hit a mechanism then it stands to reason it might be indicative - in this case if Alzheimer's is partly or fully caused by a waste removal problem in the brain.

Comment by TaupeRanger 1 day ago

The word "benefit" does not apply here. The only "benefits" patients and families care about are: 1) does the patient live longer, and/or 2) does the quality of life improve in a meaningful way? Amyloid plaques are a surrogate marker, and (as already explained by many people in this thread) have not been established as a causal factor in disease. In fact, some work has even suggested a protective role for plaques. So we do not have enough evidence to say that a 42% reduction in amyloid-beta IN MICE relays any benefit at all to humans.

You are correct that a series of clinical trials, which would take 7-10 years, would clear things up. But for now, we simply don't know.

Comment by Erem 1 day ago

> improved spatial learning by nearly 44 per cent

We care about this part

Comment by JackFr 1 day ago

In fairness to parent, while the article doesn't say the title claims 'restores memories'.

Comment by vlovich123 1 day ago

I don’t think anyone is against a treatment that works, regardless of the mechanism.

The problem is that claimed success in these rat models has never transferred to humans. Either the problem is that rat Alzheimer’s is a poor model for human Alzheimer’s or the science being done is poor quality.

> Because reducing amyloid burden is clinically proven to improve functional outcomes, these preclinical results strongly support the rationale for testing this drug in early symptomatic Alzheimer’s disease

I believe this is the critical criticism of others. There’s now two camps. One side claims that the Amyloid movement is based on faulty science and outright fraud (true AFAIK) and the other side claims that there’s still evidence the amyloid hypothesis is accurate despite the flawed start to the hypothesis (possibly true). Generally I don’t trust a lot of effort being pushed behind a hypothesis that’s got such shady behavior from proponents and that rely on fast tracking drug approvals for drugs that reduce amyloids but clearly don’t benefit Alzheimer’s. Everyone gets to choose the priors they choose to evaluate the situation on.

Comment by projektfu 1 day ago

If a beta-amyloid therapy eventually makes it to successful trials, there will still be people who believe the argument is already over and the therapy cannot work. The problem identified by Lowe and others is that some amyloid-oriented researchers were not only falsifying data but also acting as reviewers and editors of journals and tanking alternative explanations.

That has stopped, presumably, but alternative approaches haven't had much success yet either.

Comment by amluto 1 day ago

Therapies targeting amyloid deposits has been tested extensively in actual humans, and it indeed removes amyloid deposits. The main problem is that none of the therapies in question usefully treat Alzheimer’s disease.

Sure, maybe an eventual useful Alzheimer’s therapy will remove amyloid deposits, and maybe it won’t, but it needs to actually treat or at least meaningfully slow the actual disease.

Comment by anakaine 1 day ago

In all fairness the cabal was only busted up in recent years, and it was largely responsible for ensuring that alternate lines of research could never get meaningful funding by denying publishing. So where the amyloid plaque line of researxh has had decades the alternate lines of research are only really getting enough sunlight to begin growing now.

The amyloid plaque cabal has quite likely sentenced tens if not hundreds of millions of people to premature death through their actions by preventing appropriate and alternative lines of research.

Comment by aBioGuy 1 day ago

In the title "....in the APP/PS1 Mouse Model of Alzheimer’s Disease"

Given the decades of emphasis on clearing / preventing amyloids I would be fairly jaded. If someone (biotech) wants to spend $$$ chasing this down, good on them.

But a paper curing a mouse model of a human neurological disease does not move the needle for someone with or watching someone suffer from this disease.

Comment by tremon 1 day ago

> to me as an outsider the important part is a treatment that works, not why it works

Are you a mouse, perhaps? We have a plethora of treatments for mice suffering from human-induced Alzheimer's. None of those treatments have ever been shown to work for human patients, and this one is no different.

Comment by yxhuvud 1 day ago

If you read the actual article you will see this doesn't target the amyloid directly at all, but instead improve the brain/blood barrier and restore normal function of immune system, somehow.

Comment by gwbas1c 1 day ago

The podcast "Why Has There Been So Little Progress on Alzheimer’s Disease?" https://freakonomics.com/podcast/why-has-there-been-so-littl... discusses a lot of the academic fraud that lead to people following the Amyloid hypothesis.

The TLDR is that the researchers were publishing doctored images to support their hypothesises, which is why the Amyloid hypothesis was such a dead end.

Comment by pfdietz 1 day ago

Having said that, this therapy could be improving clearing of all sorts of things, not just amyloid-beta. If amyloid is just a misleading side effect, clearing it could also be misleading.

Comment by ebolyen 1 day ago

I think people are reacting to the press-release more than the work.

I don't see why this is definitely doomed just because they discuss beta-amyloid plaques. Those exist and are real. They probably don't cause it any more than tombstones cause graveyards; very related, but not in the directly mechanistic way we wish.

> Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides in the brain.

This can be true and still not be the specific mechanism.

You can treat a specific waste product or you can repair the waste stream. The issue may be waste, but not a specific product, or the issue may not be the waste stream at all.

This work appears to demonstrate evidence of waste stream repair via a well-known waste-product. That doesn't mean that any specific waste product is or is not the problem or that this particular stream is definitely going to remove enough of the waste (if that was the problem).

Maybe there have been a lot of drugs which have similarly attempted waste-stream repair so there's good reason to doubt it on that alone. But I don't think that mentioning beta-amyloid plaque is enough to discard this out-of-hand.

Comment by yxhuvud 1 day ago

It is also worth mentioning that many of the alternative explanations involve brain infection, and improving brain/blood barrier also apply to that.

Comment by layla5alive 1 day ago

A lot of people here in the comments saying 'this can't work because amyloid beta hypothesis was wrong' seem to be missing that this treatment is aimed at some of the primary mediators of general brain health (function of natural BBB/vascular waste clearance mechanisms, which seem to degenerate over time, and modulation of neuroinflammation), not just clearing AB proteins pharmacologically. This jibes well with the stated improvements in Parkinsons and ALS.

I doubt there is one root cause of Alzheimers (except maybe in some genetic cases), and this is likely not a panacea, but sounds like it may assist some of the key processes involved in breakdown.

Root behaviors related to sleep quality and quantity, diet, exercise, infection, environmental exposure and stress, as well as genetics, likely all contribute.

But, waste clearing and neuro-inflammation seem to be core processes involved in the progression of the pathology, and improving natural vascular waste clearance seems like a logical place to find at least a small improvement in progression and symptoms...

Analogy: if someone puts metal shavings in an engine, having a better oil filter won't prevent all damage caused by the person putting the metal shavings there (nor will it halt the process), but it will reduce the damage by getting those shavings out of circulation before they have a chance to make even more repeated passes through the engine and do even more more damage. Improved vascular waste clearance is likely only a small piece of the puzzle, like having good oil pressure and filtration, but that doesn't mean it's irrelevant just because it doesn't prevent the other upstream root causes!

Comment by discretion22 1 day ago

Great news! If you are a mouse.

For humans, not yet progressed to trials though safety has been evaluated for other diseases, so possible for trials to happen quickly?

" the compound has strong potential to quickly transition into human clinics because it has already undergone safety evaluations for other diseases."

Comment by smallerize 1 day ago

A genetically modified mouse with human amyloid-beta peptides. https://www.jax.org/strain/004462#

Comment by onraglanroad 1 day ago

The Hitchhiker's Guide was right. We spend all our time inventing new cures for the mice!

Comment by drtgh 1 day ago

It goes even further than that. since we don’t know what causes Alzheimer’s, what they’re doing is trying to cure their own laboratory-induced symptoms in mice. It’s like trying to fix a car’s ABS system by simulating tire slippage.

This is so obvious that the only thing I can think is that they simply don't care. They just want to find something that masks the symptoms (perhaps to keep patients dependent on the drug for life if they succeed).

What causes Alzheimer gentlemen? very few people is really trying to solve this answer.

Is it even known what causes the moments of lucidity in patients? Molecules should be mapped to identify the patterns (and therefore track possible sources).

Comment by functionmouse 1 day ago

mice are having a great year

Comment by PrincepsZero 1 day ago

I mean why not allow right to try for people who are already so far gone. It can potentially help them and all of us.

Comment by pas 1 day ago

they can try it

simply this stuff was not even at that stage. it's a lab report. there's no company making it. though there's a version of this copper complex that targets ALS, and that is already available

Comment by adamredwoods 1 day ago

Lithium, too! In mice. https://otd.harvard.edu/news/could-lithium-explain-and-treat...

Comment by helterskelter 1 day ago

Interestingly, lithium does seem to protect telomeres and in fact lengthens them, which may affect Alzheimer's.

Comment by alliao 1 day ago

interesting, I remember reading population of Beijing seem to have lithium in their water or air so their new born and mothers carrying seem to have 20x of lithium concentration of what's considered normal...

Comment by amluto 1 day ago

The papers suggest a plausible mechanism by which lithium orotate could have an effect that would be not present with inorganic lithium salts.

IIRC the hypothesis is that lithium orotate does not fully dissociate in water and thus can cross the blood brain barrier much more easily than plain Li+, and then the cells in your brain can take up the lithium orotate, metabolize the orotate part, and make the free Li+ available.

Comment by avgDev 1 day ago

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 option of a genetic test. There are several genes which increase your risk. However, if one has PSEN1 that will 100% guarantee early onset alzheimer's at some point.

I'm still on the fence if I want to know.

I really hope we get some viable treatments for this terrible disease. Early onset azlheimer's is awful. I cannot imagine having malfunctioning brain.

Comment by nphardon 1 day ago

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.

Comment by avgDev 1 day ago

She is now 63. Started showing symptoms at 61. Her sister died at 64 and her onset was in her 50s.

I am working with invitae to get her DNA tested. Unfortunately, her stage is considered moderate and very little treatment options.

Comment by armadsen 1 day ago

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.

Comment by marton78 1 day ago

Give her -- and yourself -- lithium orotate. It's an asymmetric bet: it won't hurt, but very well might help. It has been found to be effective in murine models.

Comment by xenonite 1 day ago

Yes see Dr Nehls for this.

and keto, beginning with MCT oil

Comment by armadsen 1 day ago

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.

Comment by frogperson 1 day ago

[dead]

Comment by mlmonkey 1 day ago

In some parts of the world, it is recommended that drinking water be stored in copper containers. I'm wondering if these communities had figured something out about the health benefits of ingesting trace amounts of copper?

Comment by pengaru 1 day ago

There's no need for missing answers as to why copper is appreciated as a water transport/storage medium. It's the same reason it's traditionally used as cladding on boat hulls, and is still added to many anti-fouling bottom paints - it's antimicrobial, but also toxic.

Comment by janalsncm 1 day ago

Maybe a slight problem is liver toxicity at the doses in this study? The drug was tested at lower doses for other diseases, but above 72 mg caused problems. Quick conversion math is telling me this study would want 170+ mg.

Maybe there’s some way to get around this particular issue.

Comment by mannyv 1 day ago

Anything that might fix brain plumbing would be welcome.

Over time, everything breaks down. If this actually fixes some plumbing issue that would be great. Of course, it probably will lead to another downstream plumbing issue, but one thing at a time.

Comment by djray 1 day ago

This pertinent paper appeared more than a decade ago about the flaws in the amyloid plaque hypothesis: https://pmc.ncbi.nlm.nih.gov/articles/PMC4207354/

Many people without dementia show amyloid plaques in their brains in autopsies. It's becoming more accepted now that there are multiple interrelated causes after decades pursuing the simplistic amyloid plaque theory.

The article is bordering on irresponsible.

Comment by TaupeRanger 1 day ago

Flagged. Nonsense puff piece by the university. The headline itself is beyond terrible - this is a mouse model and would need years of further successful research to be able to say that it "restores memory" in any meaningful way, let alone in actual humans.

Comment by Selkirk 1 day ago

The linked article is intentionally misleading by omission because they left out "in mice" in the university driven article and they certainly know the relevance and consequences of leaving it out.

Comment by janalsncm 1 day ago

Press release should be replaced by actual journal article, which doesn’t omit “mouse model”.

Comment by musiciangames 1 day ago

Yes, it’s really disappointing to see Monash doing that - not a mention of mouse or mice.

Comment by contingencies 1 day ago

AFAIK the background is the 'big 5' universities in Australia have a fat loan due which they took out 10 years ago and can't pay. Their primary income source was foreign exchange students and that demand has fallen off a cliff. So they're shedding academics and puffing like crazy right now. It seems in the near future Australian tertiary education will be highly corporatized and move to a more American model than our European-style history.

Comment by markdown 1 day ago

> foreign students

FTFY. Not exchange students.

Comment by contingencies 1 day ago

Erp, well caught.

Comment by phyzome 1 day ago

IN MICE

Comment by adaml_623 1 day ago

I think it's immoral and unkind to report on a medical trial and not be clear that it was in mice rather than humans.

Comment by ck2 1 day ago

btw definitely related and seems significant:

they found people who use glucosamine (joint pain, knees etc)

have a 25% higher chance of Alzheimer's progression

https://thesciverse.org/scientists-found-that-a-supplement-t...

(still can't figure out if that website is "AI" but they have great articles)

Comment by plaguuuuuu 1 day ago

Yep it's all AI-generated. It's annoying that they have a fake human as the author but whatever, it's the interslop.

Comment by littlexsparkee 1 day ago

note this is only the case for those with early-stage cognitive decline. for healthy individuals, it actually has neuroprotective effects.

> Glucosamine mimicked the effects of a low-carbohydrate diet in a prior animal research, resulting in increased lifespan [21], and studies consistently showed that a low-carbohydrate diet protects against dementia [22, 23]. An animal study suggested that glucosamine may promote cognitive function by impacting energy metabolism [20]; other animal models have indicated the neuroprotective and anti-neuroinflammatory effects of glucosamine

https://pmc.ncbi.nlm.nih.gov/articles/PMC10052856/

Comment by caycep 1 day ago

..in Mice

Comment by IAmBroom 1 day ago

"Alzheimer’s is driven by the buildup of toxic proteins called amyloid-beta."

That's the predominant theory, but nothing affecting them has yet proven to be efficacious so far (AFAIK).

Likewise, at one time everyone "knew" aluminum was a culprit, because it showed up in autopsy analyses of affected people. However, it turned out that correlation wasn't from aluminum causing it, so avoiding aluminum didn't affect the disease.