New nanotherapy clears amyloid-β, reversing symptoms of Alzheimer's in mice
drugtargetreview.com266 points by self_awareness 4 days ago
266 points by self_awareness 4 days ago
> Instead of targeting neurons directly, this method focuses on repairing the blood-brain barrier (BBB), the brain’s defence against harmful substances. By restoring proper BBB function, the researchers achieved a reversal of Alzheimer’s pathology in animal models.
Alzheimer's patients often respond positively to exogenous ketone esthers, and a ketogenic diet. The proposed mechanism for this is that ketones are transported across the BBB differently than glucose. Even if glucose is unable to be transported into the brain, ketones often still are. Now that there is a drug to repair the BBB, and likely glucose transport as well, I expect the funding will mysteriously show up to properly investigate the "brain diabetes" theory of Alzheimers.
>I expect the funding will mysteriously show up to properly investigate the "brain diabetes" theory of Alzheimers.
There was the SNIFF [0] study that delivered insulin via nasal spray, so there's already some funding and studies happening.
> Alzheimer's patients often respond positively to exogenous ketone esthers, and a ketogenic diet.
I went looking for a cite here and came up almost empty (wikipedia has one link to an 11 year old paper that doesn't really say much authoritative in the abstract).
I wish people would be more rigorous about this stuff. Atkins/paleo/keto is the gluten-free/hemp/cbd/hippy magic of the hacker set, not least because it's nearly perfect wish fulfillment[1]. And it appears in a lot of mystical contexts too, showing up as a cure for whatever is being discussed.
The actual science, every time I look, is a lot less convincing.
[1] Meat! It's all meat! We love meat!
Maybe you can see this as more compelling evidence: https://consensus.app/search/does-ketonic-diet-improve-alzhe...
>Cognitive Effects and Clinical Outcomes > >Multiple systematic reviews and clinical trials report that ketogenic diets (KD) or ketone supplementation can lead to improvements in cognitive function, daily living activities, and quality of life in people with mild-to-moderate Alzheimer's disease 413141819. Chronic KD interventions (3–4 months) have been associated with increased cognitive test scores and improved memory performance 1418. Some studies also show positive changes in Alzheimer's biomarkers, such as reduced tau and increased amyloid-beta 42 in cerebrospinal fluid 7."
Well, thanks. That's certainly better than what made it into wikipedia. But honestly: no? Only 41% of papers answering "yes" to an engaging and evocative hypothesis, in the era of the replication crisis, and especially after a decade and a half of the hypothesis sitting around in general lore, generally means "no, duh" in my experience.
As the site itself says, "evidence is still limited and more research is needed", which is definitely not "compelling". My money still sits on "nerd wish fulfillment". But we'll see.
Yeah, there are studies suggesting neurons, far more so than many peripheral cells, are especially vulnerable to insulin resistance. So by the time you see systemic insulin resistance by standard measures, the brain may already be slipping. I suppose this is why ketonic diet has any role in restoring cognitive function.
The idea that paleo/keto is all buttered meat is strange and fairly recent, with wish fulfillment probably being strongly involved. Meat would have been a luxury not available for all meals so other tissues like tendon, tripe, and skin would have been common ingredients. That plus other changes like boiling most meals and serving them with the boil water make a huge difference in the nutritional profile.
> The idea that paleo/keto is all buttered meat is strange and fairly recent
To be clear: the dietary theories here (such as they are) are surely rigorously defined and subsume all sorts of choices for how to get fats and avoid carbs.
But to a person, every solitary practitioner I've ever met has implemented their Atkins/paleo/keto diet with almost exclusively meat.
It's a MEAT! diet because nerds love MEAT!.
I read “Prolonged Meat Diets with a Study of Kidney Function and Ketosis” by Walter S. McClellan and Eugene F. Du Bois, Journal of Biological Chemistry (1930). The original paper that kicked off all the Atkins diet ideas. It made quite a point of the fact that the two men participating started off thinking that they'd like eating all meat, and quickly realizing that they began craving fat and organ meat to an extent that it ended up making up the majority of their diet.
Keto is a meat diet because you can’t find much else to eat that won’t kick you out of ketosis. Even most vegetables have too many carbs.
Paleo does not necessitate so much meat.
> kick you out of ketosis
FWIW, that notion of "ketosis" as a magical metabolic state is very much a part of the voodoo I'm talking about. The medical community does not recognize that kind of thing. Ketosis is understood broadly as a disorder along a spectrum leading to ketoacidosis, and real doctors worry about treatment.
The idea of riding the enzymes like a knife edge to hack your metabolism is very much not supported by real research and consensus, and most experts think it's borderline insane.
Perhaps, and I’m sure any diet in which you cannot eat vegetables is a bad long term idea for most people. But if you pee on the strip and it changes color you lose weight faster than caloric restriction accounts for, if you eat too many peas and it stops changing color you don’t.
So people do it, and when they do, they must eat nearly only meat because there’s not much else.
> But if you pee on the strip and it changes color you lose weight faster than caloric restriction accounts for, if you eat too many peas and it stops changing color you don’t.
And it's that logic exactly that I'm characterizing as "voodoo". You're trying to cite as obviously true what research simply hasn't shown. "I read it on a blog and it works for me" is the first step on the road to ivermectin and chemtrails.
Double blind study or GTFO basically.
I've heard the colloquial phrase "type 3 diabetes" appear a lot in talk about Alzheimers, so I'd be shocked if there isn't a lot of research going into that. I just read a book about how metabolism is related to a lot of mental disorders (depression, schizophrenia, etc.) so I think it's something that's definitely being looked at (the book is called Brain Energy, I think).
Hey what was the book out of curiosity?
Probably this one: https://brainenergy.com/
I've read it, it's quite good and full of citations. I've seen a number of studies since it came out that support it as well.
If you like that, also check out "This is Your Brain on Food" which overlaps with much of the content there, but with a bit more of a focus on the gut brain connection.
Change Your Diet, Change Your Mind is another book on these topics which is rather comprehensive and compelling.
> Now that there is a drug to repair the BBB (and likely glucose transport as well), I expect the funding will mysteriously show up to properly investigate the "brain diabetes" theory of Alzheimers
Why is this cast as conspiracy versus a natural consequence of risk and incentives? (‘Brain diabetes’ is in no way a neglected avenue of Alzheimer’s research.)
There’s been a long-running Internet movement to cast the beta-amyloid and beta-amyloid/tau hypotheses as an evil plot by scientists to siphon money away from research that works. It’s a whole thing. I anssume it’s because Alzheimer’s legitimately sucks (my mom has it) and that means there has to be someone we can blame.
It's a whole thing because there's been over a century of concerted effort in the US to cast all of science as an evil plot.
The Discovery institute, and all their donors and connections (including literal politicians) tell millions of children that science is a plot of satan to make you doubt god.
The people who created the Scopes "monkey trial" never went away, are fabulously well funded and organized and connected, and have succeeded beyond their wildest dreams
Now they are trying to expand that belief to all of academia, so that people who never set foot in an academic institution and have never tried any higher education beyond high school and have never even attempted to read a scientific paper are convinced that all Academics are in a concerted plot.
30 million Americans claim to believe God created humans exactly as they are now within the past 10k years.
That's the low estimate of christian fundamentalism and science hostile cohort in the US.
The science hostile cohort is flourishing wherever christian fundamentalism is rampant, in some places most people are exactly this. A lot of the depressing things Carl Sagan mentioned in Demon Haunted World turns out to be true. I had thought that 20 years ago we were on our way to being a rational society but it turned out this notion was on its way out.
The USA was founded by fundamentalists. They where expelled from England. They were ridiculed and called Puritans.
USA also was the only occidental country to forbid alcohol consumption, like Saudi Arabia today.
The irrational genes are in the fabric of American society.
Cmon the puritans were one of many different founding cohorts. Quakers, borderers, cavaliers, etc. America was never of one mind on the subject of religion.
I mean it doesn't help that a bunch of Harvard scientists were literally caught accepting money to shape the discussion around fat vs sugar which did irreparable damage to a generation of people.
If only those so offended by this and other (comparatively isolated) incidents, don't apply the same level of distrust of those that behave unethically and corruptly on an almost daily basis i.e. oligarchs and politicians. It's like they see a pot calling the kettle black, except the kettle is grey ("boo!") and the pot is vantablack ("I see nothing wrong here").
What on earth does the discovery institute amd creationists have to do with Alzheimer’s research? Come on. Most of the people I’ve seen criticize the amyloid hypothesis are secular.
The bigger problem and the one that is more damaging to public trust in science is actually politicians (and bureaucrats and other government and non-government institutions) who spread disinformation that policy is science. Their policy is "based on the science" they will claim, and therefore to disagree with their policy is to be a "science denier" they assert, without evidence. These dishonest interests essentially hijack the good name of science by fooling low information voters.
There is a lot of science around epidemiology, virology, vaccines, and medicine. There is no evidence based scientific consensus that it was the "correct" policy to shut down large parts of the economy, subsidize mothballed businesses, admit COVID positive patients to nursing homes, impose emergency policies impinging on human rights like restricting travel and association and medical autonomy, or fast-track vaccines for COVID.
You could argue for those policies, but it should have been completely reasonable to argue against them. That does not make you "anti-science". People can and should question the efficacy of the vaccines, and the lies that were repeated by certain "news" corporations and politicians who had interests in and donations from pharmaceutical companies, with fantastical claims about them that turned out to be false. That does not make you "anti-science" either.
Similar thing with the science of greenhouse gasses and global warming. There is a lot of science around the fundamentals of those mechanisms, there is a lot of science showing that warming can gravely damage ecosystems and human societies and therefore limiting human CO2 emissions would be a benefit. That's great, that is science. What is not science is any particular government policy purported to help this. Proposing to reduce or tax GHG emissions in one country and thereby incentivize production in another country (with far higher emissions intensity of production) is not "science". It's not "anti-science" or "climate denier" to question or disagree with a policy like that, for example.
When you say "science", you need to distinguish between science as philosophy vs. science as an institution. Science as philosophy is a way of thinking - an attempt to understand knowledge and reality. The science as an institution on the other hand has all the imperfections as any other institution, since the people in charge are driven by self interest and not just the search for the truth. So, when you say the people distrust science, it seems bizarre that they doubt science as philosophy, while in fact they doubt the institution. It's perfectly fine to mistrust the institution. If you want to consider a few failures, just in the recent years, I have some for you:
- Hungarian-born biochemist Katalin Karikó, who developed the key mRNA modification that enabled effective COVID-19 vaccines, was repeatedly denied grants and demoted during her career. She and her collaborator, Drew Weissman, struggled for years to gain recognition and funding for their work [1]
- On the other hand, the Wuhan Institute of Virology had no trouble getting grants from NIH [2]
- Surgeon General Jerome Adams was saying that masks are not effective against Covid [3]
- Social distancing was of supreme importance, until it turned out that it's fine not to distance if it's for a good cause [4]
[1] https://www.statnews.com/2022/02/01/kariko-problem-lessons-f...
[2] https://www.bmj.com/content/382/bmj.p1701
[3] https://www.npr.org/sections/health-shots/2020/07/01/8862991...
[4] https://www.politico.com/news/magazine/2020/06/04/public-hea...
> So, when you say the people distrust science, it seems bizarre that they doubt science as philosophy, while in fact they doubt the institution.
The vast, vast, vast majority of the Christian fundamentalists whom are the backbone of this movement and the subject of this discussion do not distinguish between these things. They do not distrust "big science," they distrust science, full stop. The fact that science as an institution is subject to the same corruptive forces as every other institution is a convenient post-hoc rationalization for the belief they already had and wanted to justify, just like a lot of other post-hoc rationalizations they have for other beliefs they have. They dislike science now because they are told to by their ministers, no more reason than that, and we know this because science and their religion coexisted peacefully and uneventfully for centuries until it become inconvenient for a segment of the church's politics. Excluding of course Gallileo, and for the same reasons.
Science (both as philosophy and institution) gets it wrong, but has built-in mechanisms that correct those issues. Eugenics was discredited by science. Andrew Wakefield's bullshit autism study was discredited by science. Religion gets it wrong and then calls it mystery.
It’s especially ironic to hear institutional corruption invoked as a critique of science, when many of the loudest voices in this conversation come from religious institutions that have spent decades shielding their own leadership from accountability for far more egregious abuses.
Wait, but isn't that "conspiracy" literally true? People faked data and everything...
https://hn.algolia.com/?dateRange=all&page=0&prefix=true&que...
Not sure it’s a “long-running Internet movement”. You make it sound like one of those loony anti-science conspiracist agendas. There have been a lot of serious articles written about it. I don’t think it’s hard to believe that a lot of scientists and institutions have the incentive to try to keep a whole system of focusing on removing beta-amyloid going as a self-fulfilling cycle. Getting funding and publication citations snd promotions etc. could always be the fundamental incentive out there.
Sabine Hossenfelder uncovered a whole industry in theoretical physics.
did she? or is she simply preaching to a certain choir that's awash with the heavy anti-establishment and anti-intellectual sentiment of nowadays?
https://www.youtube.com/watch?v=miJbW3i9qQc
https://www.youtube.com/watch?v=70vYj1KPyT4
... that said, of course there's some valid criticism of science funding underneath, and (the whole role, purpose, and status of) the academic sphere (with its traditions and privileges) which largely determines the outcome of how grant organizations end doing funding decisions.
I've been doing research as a post-graduate and I can definitely say that a big part of academia is just an echo chamber for what is mainstream. Mainstream is not necessarily bad. But the echo chamber happens uncritically and even in bad research. It is frightening at least.
the problem is that ... there's currently no better theory that matches the data than the amyloid cascade one - as far as I understand (and of course I'm extremely far from an expert on this)
still, I think it's correct to state that it's very hard to falsify the hypothesis, because it says that AD (Alzheimer's disease) goes through the following stages: unknown proximate cause leads to appearance of amyloid plaques which then irreversibility lead to Tau bundles (tangles) which inevitably lead to neurodegeneration which then show up as AD
the model states that by the time the plaques are there it's "too late"
of course there are drugs being tested to try to "solve" this from multiple angles, for example make the progression slow enough to "not matter", prevent the tau bundles, etc.
...
https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
see also "In 2024, the amyloid-cascade-hypothesis still remains a working hypothesis, no less but certainly no more": https://www.frontiersin.org/journals/aging-neuroscience/arti...
in particular I recommend looking at this diagram that shows how the model has evolved over the decades: https://www.frontiersin.org/files/Articles/1459224/fnagi-16-...
> There’s been a long-running Internet movement to cast the beta-amyloid and beta-amyloid/tau hypotheses as an evil plot by scientist
No one was twirling their mustache trying to make people suffer. Someone had a lab, and prestige and control over funding and the best way to keep it all was by being dishonest. That negatively affected progress in the field. You can call it "evil" if you want, but more objectively it was unaligned incentives. The corruption was covered in mainstream news, it's not a conspiracy theory. Since the scandal got out, the speed of progress has improved significantly.
> You can call it "evil" if you want
It was a concerted and intentional effort to fake data and falsify research into a pervasive deadly disease, specifically in order to hoard funds going to research they knew was, if not a dead end, at least not nearly as promising as they were claiming, preventing those funds from going to other research groups that might actually make progress, essentially stealing donations from a charity, and using their power and clout to attack the reputations of anyone who challenged them. They directly and knowingly added some X years to how long it will take to cure this disease, with X being at least 2 and possibly as much as 10. When Alzheimer's is finally cured, add up all the people who suffered and died from it in the X years before that point, and this research team is directly and knowingly responsible for all of that suffering. Yes, I think I will call it absolutely fucking evil.
Yes, I share some of your concerns about groupthink and research cliques. The best and balanced critique is Karl Herrup’s book at MIT Press: “How Not To Study a Disease”.
Your comment is over the top with respect to NIH-funded researchers doing Alzheimer’s research. The emotion would be entirely appropriate if directed at RJ Reynolds Inc. and other cigarette companies or Purdue Pharma. Those are evil companies that many governments have tolerated killing for profit—Purdue Pharma and the OxyContin disaster alone about 500,000 Americans over 20 years; and US tobacco companies contribute to about as many excess deaths per year.
The systematic image manipulation by a postdoctoral fellow, Dr. Sylvain Lesné, was egregious and worthy of jail time but he was a truly exceptional case and polluted 20 or more papers that did distract the entire field. You can read all about it here.
PMID: 35862524 Piller C. Blots on a field? Science. 2022 377:358-363. doi: 10.1126/science.add9993
Again, I urge you to read this article and stop promoting conspiracy nonsense. I take this very personally because my mom has this disease, and people who clearly don't understand what they're talking about fuming about conspiracies really doesn't help anyone, and probably hurts them immeasurably. https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
I really urge you to read this article. It was posted elsewhere in the thread as well: https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
I can't guess what point you're trying to make with a long article that acknowledges the fraud in the beginning, and then rehashes the initial reasons for looking into the amyloid hypothesis. No one is claiming it was stupid to look into the amyloid hypothesis. They are complaining that it hasn't been the most promising theory in quite a long time, and it was fraudulently held as the most promising. Other theories, arguably more promising, are listed throughout your article.
There is a testable prediction in your article. Unfortunately, I don't think the mechanism is quite restricted enough. TFA says that repairing the BBB helps amyloid plaque clearance. Would the author of your blog post claim that as a win, or admit that the plaques are downstream of the problem, and that BBB integrity is closer to the root cause of the disease process?
Unfortunately, I don't think the mechanism is quite restricted enough. TFA says that repairing the BBB helps amyloid plaque clearance. Would the author of your blog post claim that as a win, or admit that the plaques are downstream of the problem, and that BBB integrity is closer to the root cause of the disease process?
The author of that blog post, for whom I am in an excellent position to speak, would point to the "sole intended mechanism" clause in the testable prediction. That is, if the therapeutic's developers do not claim any other intended pathway for clinical benefit from improved BBB integrity other than amyloid−β clearance, then it would count. If not, then it would not count, even if it's plausible or even likely that that's the main pathway by which the benefits are accruing.
However, because this is early preclinical research, it's not likely to reach a late-stage clinical trial within the 12-year window of the author's prediction. Furthermore, in every year there are about a dozen of these preclinical studies that go viral for some reason or other, often having little correlation with how promising the science is. I haven't had a chance to look into this one in detail, so this isn't a negative comment about it, but the base rate of this stuff panning out is low, even if it's good research.
The author of that article would also point out that the concept of "the root cause" isn't terribly well-defined, but that strong evidence points to amyloid pathology as the common entrypoint in all cases of Alzheimer's disease, even if multiple upstream factors (some possibly relating to the BBB) can feed into that, depending on the specific case. Similarly, calorie surplus causes obesity in nearly all cases, but the specific cause of calorie surplus may vary from person to person.
I can't guess what point you're trying to make with a long article that acknowledges the fraud in the beginning, and then rehashes the initial reasons for looking into the amyloid hypothesis. No one is claiming it was stupid to look into the amyloid hypothesis. They are complaining that it hasn't been the most promising theory in quite a long time, and it was fraudulently held as the most promising. Other theories, arguably more promising, are listed throughout your article.
A correction: the article does discuss other hypotheses, in pointing out that they can't account for crucial evidence, whereas there isn't any major evidence the amyloid hypothesis seems to have trouble accounting for, and it thus remains very strong.
If that's not evil to you, everything wrong in your world must just be misaligned incentives.
> No one was twirling their mustache trying to make people suffer. Someone had a lab, and prestige and control over funding and the best way to keep it all was by being dishonest.
The second sentence and the first sentence are merely literal and figurative descriptions of the same activity.
Also, for this to be true, it has to mean lab workers knew about progress but fucked over their own family with Alzheimers. And it has to mean every single one of them did this.
*Edit* Actually there's another way to interpret what you wrote. My mistake. I imagined a scenario where someone knew of progress and was dishonest by hiding it, but you might've been alluding to someone knowing an avenue wasn't fruitful but was dishonest by making it seem more fruitful.
I think the latter is easier to hide than the former since it doesn't require directly fucking over your family, merely very indirectly by siphoning off a fraction of total funds to be flushed down the toilet.
The latter is what happened, for upwards of ten years. And it wasn't a small fraction of the funding -- almost no funding was allocated to any research not looking at amyloid plaques, because the intellectual giants' (falsified) research was showing that that was by far the most promising avenue to explore.
Again, there were a couple of instances of fraud in one sub-branch of a sub-branch of a field ages ago, and The Internet has decided to turn it into a conspiracy theory.
On the off chance that you're actually a decent, honest person, I urge you to actually go learn about this theory that you're promoting. Go out and actually figure out the truth, because if it turns out that you're wrong about the impact and intentions, you're helping to harm a lot of people.
Wait… so the call doesn’t come from inside the building?? It’s crap leaking in from the rest of the body?
That’s wild.
Would it be possible to artificially increase the glucose in the brain to get a nootropic effect?
Wasn't it revealed that the research supporting amyloid-beta plaque as the cause of Alzheimer's was fraudulent? https://www.science.org/content/article/potential-fabricatio... https://www.science.org/content/article/alzheimer-s-scientis...
This therapy doesn't target the amyloid-beta plaques. It repairs the blood brain barrier, and then the body is able to clear away the plaques. Their buildup is a symptom of Alzheimers, not the cause.
The problem with the amyloid-beta hypothesis was the assumption that these plaques were causing the Alzheimers and that removing them by itself could lead to a cure.
Exactly this. Amyloid-beta plaques and their association with dementia were discovered early on (late 1800s/early 1900s https://en.wikipedia.org/wiki/Amyloid_plaques#History), but the theory that they cause dementia hasn't panned out.
While the article emphasizes the BBB repair aspect, it seems the treatment does ultimately target plaques directly at a mechanical level:
>Normally, the protein LRP1 acts as a molecular gatekeeper, binding to Aβ and transporting it across the BBB for elimination. In Alzheimer’s, this system becomes fragile, leading to Aβ accumulation. The supramolecular drugs mimic LRP1 ligands, binding to Aβ and initiating its clearance, effectively resetting the system and restoring vascular function.
My sense of the narrative is that "unclogging" the amyloid protein with this treatment allows innate repair functions to resume.
I think amyloid being the proximate cause of neural degeneration in moderate and severe Alzheimers is basically disproven at this point.
I still think it's more likely than not (70%) that it is a cause though farther upstream. There is a good amount of evidence tau is more likely the proximate cause due it more closely tracking disability in moderate to late stage Alzheimer's.
Whoa there. Is that what’s happening? Cause an alternative theory is cause -> plaques -> cognitive disease. You seem to be arguing cause -> cognitive disease -> plaques, and I’m not sure this research demonstrates that. Does it?
I think they're arguing
Cause -> cognitive disease Cause -> plaques
That is, that the same cause is behind both.
There may be some arrows from plaque to disease as well (i.e., that plaques also increase disease).
I dont know the truth, but just trying to understand/follow Alzheimers news and reading comments.
Why does it seem like they're arguing that? I think that it's supposed to really be: cause -> (plaques = cognitive disease), and the fraud was (cause = plaques) -> cognitive disease.
As I took it, understanding that there was a fraud doesn't mean that continually clearing the plaques wouldn't have a good chance of holding off cognitive disease indefinitely.
I'm simply arguing that the plaques could be the proximate cause and the problem addressed by this treatment could be the remote cause. The OP is being vague in the way they stated it, but it feels like they're saying the plaques are irrelevant. That doesn't seem to fit what we know: the evidence that cognitive symptoms are downstream of plaques is pretty compelling.
I also don't think "fraud" should be used in this discussion at all.
With all that said, if this One Weird Trick can clear/prevent the buildup of plaques (and thus the cognitive symptoms downstream of them), that's just a best possible outcome.
This article: https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h... makes a pretty compelling argument for continued research on the link between amyloid-beta and Alzheimer's.
This article is incredibly informative and I wish the folks in this thread would read it. Doesn’t make the current result any less exciting.
Not saying it’s wrong or worthless, but do keep in mind that neither the author not the blog owner is in the medical field. That post is an outsider’s read of the consensus opinion from their investigation of the literature, including an estimate of the strength of that literature formed without expertise in the field itself.
It's correlated, much as body temperature is correlated with infection. But much like lowering body temperature won't cure the infection, directly addressing the amyloid-beta plaques doesn't seem likely to directly address Alzhimer's. Addressing the actual root cause may also make the plaques go away.
FWIW the article says this:
>"The long-term effect comes from restoring the brain’s vasculature. We think it works like a cascade: when toxic species such as amyloid-beta (Aβ) accumulate, disease progresses. But once the vasculature is able to function again, it starts clearing Aβ and other harmful molecules, allowing the whole system to recover its balance. What’s remarkable is that our nanoparticles act as a drug and seem to activate a feedback mechanism that brings this clearance pathway back to normal levels,”
>...
>Normally, the protein LRP1 acts as a molecular gatekeeper, binding to Aβ and transporting it across the BBB for elimination. In Alzheimer’s, this system becomes fragile, leading to Aβ accumulation. The supramolecular drugs mimic LRP1 ligands, binding to Aβ and initiating its clearance, effectively resetting the system and restoring vascular function.
So we may be lucky in that addressing the plaques as a symptom does indeed (allow for) repair of the underlying cause. I guess the question is how long the benefit lasts. What triggers the negative feedback loop in the first place? The article claims long term improvement for the mice, which were genetically programmed for amyloid production. (So maybe not an accurate simulation of the root cause, but perhaps actually more of a steel man test.)
I'm not a neuroscientist, but it seems that hypothesis existed before that paper and has more supporting evidence than what's been retracted: https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_...
It's most likely highly correlated, but not causative. That correlation still makes it diagnostically useful, which is how it's used here.
It's very likely causative. There is just too much evidence for it not to be. All the genes related to amyloid processing are correlated with Alzheimer rates.
The most likely theory I've seen is amyloid causes tau buildup which leads to the majority of the damage. And by the time they give anti-amyloid drugs it's too late and the tau is doing the majority of the damage.
An analogy would be if you have a hole in your house which leads to getting a rat infestation. Once you notice the rat infestation patching the hole isn't going to solve your problem. The hole caused you to get rat shit on your counter, but by the time you fix the hole it's too late to stop the rats from shitting on your counter.
I thought amyloid-β buildup is usually determined at autopsy? That's not really the kind of diagnostic medicine I'm looking forward to. Can it also be determined via brain biopsy?
You can do PET imaging for it--there are a bunch of 18F-based tracers that work reasonably well. It also inversely correlates with Abeta levels in the CSF. Ne
Neither of those are particularly easy procedures, but certainly better than a biopsy (and autopsy!)
There were some important papers that turned out to be fraudulent, but there is a large and broad body of knowledge supporting this link.
Here's a good article which explains the remaining arguments in favour of the amyloid hypothesis: https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
Fraudulent research should be treated as no-info, not a negative signal on the target. You can have fraudulent research supporting a correct theory. In fact this is more common, people will generally fake evidence to support a theory they think is probably true.
Yes, in a sense... but that doesn't mean amyloid-beta is an irrelevant therapeutic target. It's a bit more complicated.
IIRC, it was revealed that treating this as a cause is wrong, it complicates or causes dementia, but is a symptom of something else, not a root cause of the disease.
But treating symptoms, esp restoring cognitive function, is a good thing.
This scandal comes to mind any time I see amyloid plaque research. Not sure if I misunderstood the scandal or if Alzheimer’s research has too much momentum to pivot. My dad was diagnosed a few years back and seeing stuff like this is always encouraging and infuriating because of this science article.
For one hundredth goddamn time: Mice don't have Alzheimer's. They can't ever get it and almost none of the successes scientists achieve with the mice illness that has nothing to do with Alzheimer's except similar symptoms are reproducible in humans at all.
I really wish the news sites would get it correctly from time to time, this is misleading as hell.
> The researchers tested their approach in mice genetically programmed to overproduce Aβ and develop cognitive decline similar to Alzheimer’s pathology.
Thoughts on that FTFA?
People are criticizing mouse models of AD. There is understandable given the confusion of the roles of animals models in disease. Let me explain:
First, the very name, ‘animal model of disease” is misnomer, and the cause of most of the confusion. Animal models are more accurately described as ‘models of mechanism’.
Second, while mouse are different from humans and how a disease manifests is different as well, many of underlying mechanisms that drive a disease share strong similarities across species. Mice, rats, dogs, pigs, humans etc… all share the same fundamental building blocks and cellular/tissue/organ mechanisms. Studying how a disease or even partial aspects of a disease manifests in, say, a mouse, can offer extraordinary insights in how the disease may manifest in humans. This can provide a strong experimental basis for potential therapies in humans. (A rough analogy is the field of software is that different programs can use the same functions. Understanding how a function is misbehaving in a simple program can provide insights in how it is misbehaving in a more complex program.)
Third, many diseases are difficult or impossible to study in humans. Alzheimer’s is a good example as the progression occurs on a timescale of decades. Further, we obviously can’t go around cutting out brain tissue from live humans.
It’s a big topic, but hopefully my brief outline provides some context for the use of animals models. We scientists also use cell and organoid models, which, while lacking key details of animal models in unknown ways, can provide insights as well.
I think the main progression is lymphatic dysfunction > chemical build-up > BBB damage > neurodegenerative plaques and tangles.
My mother died from Alzheimer's at 77 but was the picture of health and happiness for many years prior, but never slept well to the point she had to have her own room away from Dad for many years.
Maybe the trick is going to be repairing the BBB and stimulating lymphatic function rather than chasing down every factor that explains why the BBB and/or lymphatic function is compromised in the first place.
I think the cure is going to be something that dissolves tau tangles, or something safe enough we can give as a preventative to people 10-20 years before they develop symptoms that helps with amyloid.
The authors of this work believe the treatment enables BBB repair and restoration of healthy vasculature.
Mice get all the big health discoveries.
We're going to be ruled be a race of super healthy, immortal, super intelligent lab mice.
Original article was posted on HN: https://news.ycombinator.com/item?id=45508672
From 2023: It has been suggested that the BBB breakdown may precede cognitive decline and neurodegeneration, highlighting the critical need for further exploration of the BBB’s role in AD and its potential as a therapeutic target [22]. The BBB endothelium is a specialized system of brain microvascular endothelial cells that separate circulating blood from the brain’s extracellular fluid, maintaining the brain’s homeostatic environment [23]. The BBB endothelium plays a crucial role in the protection and functioning of the brain, allowing the selective passage of nutrients and molecules essential for brain function while simultaneously preventing the entry of potentially neurotoxic substances [22].
Also interesting: the two-hit vascular hypothesis of AD suggests cerebrovascular damage (hit 1) as an initial insult that is self-sufficient to initiate neuronal injury and neurodegeneration. Additionally, it promotes the buildup of Alzheimer’s Aβ toxin in the brain (hit 2)
The paper: `Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood–brain barrier transport` https://www.nature.com/articles/s41392-025-02426-1
"Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment."
I'm curious if Derek Lowe will comment on this on his blog. I'll await his opinion on how much we ought to celebrate here. He's not a big fan of the amyloid hypothesis and has worked many years in this exact field, so I reckon he will point out why skepsis is warranted.
Yup. I hope he says something about what "nanotherapy" means.
My biggest criticism of the article is emphasizing "nanotechnology" when it is really just an extra large synthetic molecule.
I mean, it is nanotech! But just not the type most readers would imagine. They could have elaborated on an justified this better by explaining novel synthesis method or something.
If the causal mechanism in Alzheimer's is not clear, what's to say it isn't about 20 or 20000 different things going wrong in ways and proportions which are very specific to each individual?
I'm not criticizing basic research, which I consider immensely useful. Rather, the way we expect for it to become magical drugs. The peak of contradiction is posing that humans are inscrutable creations of God who wills us to age and die miserably, and in the same breath also wanting to have a neat repair handbook indicating fixed doses of the same drugs for each symptom--as if we were some cheap car model that comes without spares nor OBD port, and that it's only serviced at the end. I think we need to solve that.
> what's to say it isn't about 20 or 20000 different things going wrong
In this case, the therapy resulted in old mice performing like young mice (in addition to the amyloid-beta level reducing).
Well they synthesized a magic molecule that mimics an endogenous compound that stops functioning in the diseased systems.
Everyone agrees with you. The whole era is "precision medicine".
from the bbb wiki:
There is also increasing evidence that a healthy gut microbiome is necessary to maintain BBB integrity, both in development and aging.[38][39][40][41]
I'll drink to that (kefir)!
"reversing Alzheimer’s in mice"
is a bit of a clickbait stretch. Treatments in humans targeting amyloid have failed to have much effect on Alzheimer's.
(N+1)th time's the charm!
I do sincerely hope that we find something for Azheimer's, but there's just a mountain of data suggesting that mouse models of Alzheimer's and/or ABeta simply not that useful.
The headline really, really annoys me. It makes it sound causal, amyloid-B removal causes reversing symptoms of alzheimer's. Thus supporting and even making seem certain the still somehow overwhelmingly popular (not to sound like conspiracy anti-pharma guy(1)) amyloid theory of alzheimers.
All this shows is that one of the effects of the treatment is clearing aggregates, IN MICE. That's it, nothing more.
We don't know for sure the causal mechanism. There was/is a fanatical well-funded machine behind the amyloid hypothesis; that doesn't make it correct. There is much reason to doubt it or at least downgrade it to a contributing but not sole causal mechanism.
(1) it is absolutely mind-boggling to me that the amyloid clearing drugs like Aduhelm got FDA approval while so many much more proven treatments for other diseases sit waiting.
Why isn't "in mice" an automatic flag for posting? This is not a breakthrough in Alzheimer's nor is it headline news in Alzheimer's research.
I emphatically support flagging all "medical" articles in which mice are the only species used as a disease model.
I asked this question in Ask HN about six months ago but received little support and much criticism.
Why should it be? Because of lacking relevance? The community can find even research in mice interesting - look just how much debate has this topic produced here. We're not an Alzheimers research forum, we are a bunch (tribe? murder?) of nerds who like to gab about new things.
You'd have a better point if the "in mice" was hidden somewhere in the text - for subtle dishonesty, but as long as the title admits it openly, I don't see a reason to flag the submission in itself.
If it's the removal of the proteins not the plaque I wonder if that's the cause of people chasing the plaque for years? Classic correlation causation problem if so... Time to go read
So, yet another experiment that points to vascularization problems as the root cause of dementia.
You know what? Some studies (not all) have shown association of Viagra use with a reduced risk of Alzheimer's. That would fit into the picture. Viagra was originally intended to treat high blood pressure and heart disease.
Yes, we have a mouse model of Alzheimer's that can be cured by preventing amyloid beta buildups. And billions of dollars in failed drug trials demonstrate that what works for those mice, doesn't work for humans.
This has been demonstrated for many years. And yet we waste literally billions per year researching treatments that will only work in mice. And yet we regularly publish articles proclaiming that we can cure mice, humans are next!
This research is BS and a waste of taxpayer money.
In general I do not think that a research which does not lead to a full resolution of the primary issue can be dismissed just because it does not actually resolve the issue.
Every step of the way towards the resolution of the issue is important. Even ruling out what does not work is important.
Without those incremental advancements, we may never reach the end goal.
Of course we should try to learn from past research.
But sometimes the lesson to be learned is that what we were is a bad approach, and we need to rethink things. We can't simply run experiments and get results. We also need to study whether our experiments are telling us what we think that they are telling us. Because if we don't know what our experiments are actually telling us, we're going to misunderstand the results.
https://people.cs.uchicago.edu/~ravenben/cargocult.html is worth a read on this. Among other examples, it includes an explanation of what actually has to be done in order for a rat running a maze to actually test the rat's memory. And how it is that we know that this is what has to be done.
The fact that psychologists ignored that experimental procedure marked psychology as a cargo cult science. (Some 40 years later, the replication crisis forced psychologists to at least talk about the issues that Feynman raised...)
The fact that we continue testing animal models of Alzheimer's that we have proven to be a bad model of humans, likewise shows that Alzheimer's research has become a cargo cult science.
>The fact that we continue testing animal models of Alzheimer's that we have proven to be a bad model of humans, likewise shows that Alzheimer's research has become a cargo cult science.
Partially. It also, more primarily, shows that medical funders and ethics committees demand very strong evidence in one animal model before they allow you to move a step "up the ladder" towards humans. What you can test on mice, you haven't managed to get approval to test in nonhuman primates. What you can test in nonhuman primates, you might get approval to test in humans. What you can test in humans, might finally prove useful for treating humans.
But the broad assumption is that if something fails in mice, we can know it would have been unethical to try it on humans first.
Billions of dollars leading to failure during clinical trials is the overwhelmingly likely outcome for all therapeutic areas, particularly so for CNS.
Somebody else asked "what is your alternative?" and you responded with "drunk under a streetlamp". The issue with this is that all of science is drunks under streetlamps. Scientists rely on a set of methods; for preclinical work, this is animal models, organoids/tissue chips (still in development), and in-silico AI stuff. Slim pickings! To use your lamp analogy, all of these options will give off a pretty dim amount of light.
What evidence would it take for you to reconsider how we are approaching Alzheimer's?
Our working theory is that amyloid beta plaques cause Alzheimer's, and so preventing them will prevent the disease. We have absolutely demonstrated our ability to prevent those plaques in both mouse models and humans. Doing this cures symptoms in mouse models. It does not cure symptoms in humans. I already gave a list of 9 different approaches that generated this exact result. How many more billions do we need to spend on new approaches to do the same thing, before the field reconsiders the theory?
And the failure here is not just with failed drug trials. In this century, it is easier to find fraudulent data advancing the hypothesis, than real data. With the result that several fraudsters have managed to create very good careers for themselves before being caught. This is a sign that there is something very deeply wrong with the field, if such fraud is rewarded rather than being caught more promptly.
Furthermore you are absolutely wrong about what I said about the alternative. My drunk under a streetlamp comment was about continuing to use these animal models to create more drugs. My suggested alternative was basic science. If amyloid beta plaques are a symptom, not a cause, of Alzheimer's, then what is the cause? We need to figure that out, before trying to create new drugs for it.
And it isn't like basic research has nothing to try. Alternate hypotheses with some suggestive data for them include Tau folding, inflammation (possibly caused by viruses), problems with the blood-brain barrier, problems with the mitochondria of neurons, dysregulation of metal ions, and so on. Maybe the real answer is not even on this list. But finding and demonstrating the real cause should be a high priority.
My father-in-law has Alzheimer's. If research continues for the next 30 years like it has in the last 30 years, there will still be no treatment when my wife gets old enough to worry about getting it. This is not a potential future that I'm particularly looking forward to. (But maybe I'll get lucky and get it before her...)
The researchers, as quoted in this article, view their work as a step towards understanding the interplay between amyloid proteins, the BBB, and cardiovascular dysfunction. That sure sounds like an interesting step towards deeper root causes.
The fact it has to be done with mice is the best we can do. The article also does not elaborate on what interesting modeling or synthesis techniques might have been used, which could be more generally applicable.
> then what is the cause? We need to figure that out, before trying to create new drugs for it.
Isn't that what the animal experiments are for? Trying to find causation?
Isn't it often even worse in that many of the "models" are intentionally inflicting a condition superficially similar to a symptom, and then showing some treatment blocks or reverses that? So sometimes nothing to do with the underlying disease.
The NIH recently changed their grant funding policy to focus more on human experiments instead of animal models. It will take some years to see whether this change has any positive or negative effects.
https://grants.nih.gov/news-events/nih-extramural-nexus-news...
Yes, this is exactly the problem with animal models. We can tell that the animal has the same symptoms. We don't know that it has it through the same pathway as humans.
The models have worked often enough that it is reasonable to hope that what works in animals, will work in humans. And it is easier to experiment on animals. This is why they are used in research.
But when what works in animals doesn't work in humans, repeatedly, we should stop using that animal model in research.
Here are examples of treatments for Alzheimer's that worked in animals, reached human trials, then failed to help humans: AN1792 (active Aβ vaccine, Elan), Tarenflurbil (R-flurbiprofen), Semagacestat (γ-secretase inhibitor), Bapineuzumab (anti-Aβ mAb), Solanezumab (anti-Aβ mAb), Crenezumab, ponezumab, gantenerumab, and BACE inhibitors (e.g. verubecestat, atabecestat).
All of these were considered promising enough in mice to be worth expensive human trials. Where they failed. Those weren't cheap failures, either.
You've certainly got a point that if mice cannot and do not develop Alzheimer's naturally, we should use a model organism that can.
Okay but how exactly should researchers come up with drugs to try on humans then?
There are other animal models, some of which even seem to develop dementia-like symptoms spontaneously.
Mice have absolutely dominated research because they're relatively cheap, lots of powerful genetic tools are available, and the PR is more tractable. However, that doesn't mean they're the right choice for every experiment.
I mean my question genuinely. I have no attachment to using mice, I just wasn’t hearing any solutions from the parent comment.
This argument is like the infamous drunk who was arguing that he should continue looking for his keys under the street light, because the place where he actually dropped them had no light so he couldn't see.
At this point it is a waste of time and money to produce more drugs that are guaranteed to fail in humans. Making it harder to waste time and money in this way is a feature, not a bug.
After we have better basic science about what likely causes Alzheimer's, we can go back to the question of how to find drugs that might help. Trying to do it in the other order is putting the cart before the horse.
It's more like the drunk is using his dim phone screen to illuminate the ground, and someone shouting to him, "hey bro a helicopter mounted searchlight would be better!"
We have to make do with the tools available to us.
The litany of posts you’ve made in this thread indicate that you’re passionate about this topic.
Sincere question: wouldn’t the great energy and intensity you’re putting into web forum replies be better channeled into Alzheimer’s advocacy?
Research into medicine that make the blood/brain barrier function like on healthy people will certainly find applications though, regardless of if it is useful against Alzheimers though.
Perhaps you would like to volunteer as a test subject instead?
That wouldn’t work, the test subject needs a brain.
(Sorry, this is a rude joke. Truthfully my disagreement with patent is only medium-strength. I just can’t resist jokes.)
Are you a dad by any chance?
No, but I have nothing against them. Hell, I’m half dad on my father’s side! :D
This is a nonsequitur and an ad hominem.
Did you have a substantive response? Or are you just here to deliver meaningless snark?
It is neither non sequitur nor ad hominem. Look those up (or ask chatgpt to do it for you).
But in case it isn't clear: All models are inherently imperfect. That doesn't mean they aren't useful. The ideal test subject tends to complain when you propose dissecting their brain for analysis.
I will not bother to respond to you again.
Instead I will trust that those in the audience that I might care about, can judge your lies and insults correctly.
So you propose to replace mice with... increased nonhuman primate testing, right?
Right?
Until we can build human organlets to make experiments on them, mice are the cheapest lab animal. How do you want to avoid using them?
Though I would say that creating a pseudo-human brain in a vat and giving it Alzheimers would be pretty controversial.
"we waste literally billions per year researching treatments"
Sir, do you realize that in science, you principially DON'T KNOW IN ADVANCE WHAT WILL WORK AND WHAT WON'T?
Yes, we could experiment on primates instead, but in that case, be prepared to shell maybe thirty times as much money for the same research. Mice are cheap. Monkeys are not.
