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▲Copper transport drug restores memory and clears toxic Alzheimer's proteins (<a href="http://www.monash.edu" rel="noopener noreferrer nofollow" target="_blank">monash.edu)
Rendered at 01:47:57 GMT+0000 (Coordinated Universal Time) with Cloudflare Workers.
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...
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...
"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.
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.)
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.
>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.
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.
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.
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.
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.
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.
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.
It's time for the inflammation / diabetes / infection / metabolic dysfunction / liver dysfunction folks to get more money to test their theories.
https://stanforddaily.com/2023/12/31/blockbuster-alzheimers-...
https://news.ycombinator.com/newsguidelines.html
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.)
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.
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.)
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/
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?
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.
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.
As you have demonstrated an interest in this topic, but are not an active researcher, I suggest that you become familiar with Alzforum [www.alzforum.org]. It provides reputable summaries and comments from leading researchers on topical issues and papers in Alzheimer's and related neurodegenerative diseases.
They're still fairly technical, but not as dense as the original papers. Here is an example related to our discussion: https://www.alzforum.org/news/research-news/app-c-terminal-f...
I actually read your article some time ago, having found it via SSC. One comment I would make is that the pathology and genetics of AD implicate APP without much doubt. In the field, there isn't much argument against it, even by those who work on tau. Divergences in opinion more often focus on which is the better target for drug therapy.
For example, Derek Lowe's articles on AD do not argue against an APP-tau-neurodegeneration pathway (I am a regular reader of his blog), but argue that targeting amyloid is unlikely to work as a drug therapy. This argument is sometimes extended by Lowe and others to questioning whether Aβ per se is the agent that triggers the downstream effects of either mutating APP or otherwise disrupting its biology. It is possible that Aβ is a by-product of the "true" APP-triggered pathway, see the arguments in favor of C-terminal fragments I linked to earlier.
A fundamental problem the field faces is that it is difficult to experimentally induce actual AD in animals, and so it is difficult to scientifically test hypotheses as to what might cause it. Compare perhaps to something like diabetes. Exactly why mice do not develop realistic AD is unknown.
In addition, there have been literally hundreds of publications (minimum 300) claiming to reverse "Alzheimer's disease" in mice, and the only ones that have lead to any kind of meager success are those using the antibodies. The arguments made in the 2010 review below by Zahs and Ashe [0] remain mostly true sixteen years later.
The recent clinical trials, e.g. Lecanemab, are of interest not only because they might provide at least some benefit, but also because they might represent the first actual scientific experiments showing that removing Aβ can ameliorate the disease, even if only slightly because of the late stage at which they have so far been tested.
Currently ongoing trials using anti-Aβ antibodies and targeting earlier phases of the disease in those with inherited mutations are of keen interest. If these demonstrate clear prevention of disease progression, then the Aβ hypothesis can be considered tested and proven. If not, then the Aβ hypothesis should be abandoned. This would however still not disprove an APP-focused hypothesis.
[0] 'Too much good news' - are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer's disease? https://alzped.nia.nih.gov/sites/default/files/2022-09/zahs....
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/
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.
This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article.
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.
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.
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.
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.
Brush and floss bruddahs.
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.
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.
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.
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
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.
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.
EDIT: They edited their message to reflect that
Come on, he's a software engineer, a little reading will give him a shit-ton of confidence.
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).
That last part isn't a sidenote, it's the entire reason for discussing the theory.
"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.
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.
> 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...
But again I am not saying you are wrong and I am even sympathetic to this narrative but ultimately, unconvinced, either way
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.
https://a.co/d/0cXTgHgv
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.
[1] https://www.science.org/content/blog-post/things-i-won-t-wor...
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.
I almost couldn't believe we are still talking about the same causes of alzheimers 16 years later.
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.
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.
https://www.salk.edu/news-release/in-surprising-twist-some-a...
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.
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.
So there's some benefit. Sounds like their next step is a much larger trial to answer the question you are posing.
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.
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.
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?
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.
We care about this part
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.
That has stopped, presumably, but alternative approaches haven't had much success yet either.
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.
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.
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.
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.
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.
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.
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!
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."
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).
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
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.
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.
I am working with invitae to get her DNA tested. Unfortunately, her stage is considered moderate and very little treatment options.
and keto, beginning with MCT oil
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.
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)
> 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/
Maybe there’s some way to get around this particular issue.
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.
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.
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.
FTFY. Not exchange students.