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 popular (not to sound like conspiracy anti-pharma guy...) amyloid theory of alzheimers.
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.
All this shows is that one of the effects of the treatment is clearing aggregates. That's it, nothing more.
> 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'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).
> 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.
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.
>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.
> 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.
> 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.
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.
> 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.
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.
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?
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.
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!)
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.
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.
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.
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.
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.
"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.
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.
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.
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...)
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.
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.
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.
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.
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 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 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.
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.
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
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.
All this shows is that one of the effects of the treatment is clearing aggregates. That's it, nothing more.
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.
There was the SNIFF [0] study that delivered insulin via nasal spray, so there's already some funding and studies happening.
[0] https://www.clinicaltrials.gov/study/NCT01767909
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!
>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."
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.
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.)
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.
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.
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.
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.
https://hn.algolia.com/?dateRange=all&page=0&prefix=true&que...
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.
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.
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.
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.
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.
Neither of those are particularly easy procedures, but certainly better than a biopsy (and autopsy!)
https://pmc.ncbi.nlm.nih.gov/articles/PMC3264790/
But treating symptoms, esp restoring cognitive function, is a good thing.
I really wish the news sites would get it correctly from time to time, this is misleading as hell.
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'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.
In this case, the therapy resulted in old mice performing like young mice (in addition to the amyloid-beta level reducing).
"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.
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.
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.
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...)
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.
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.
https://grants.nih.gov/news-events/nih-extramural-nexus-news...
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.
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.
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.
Sincere question: wouldn’t the great energy and intensity you’re putting into web forum replies be better channeled into Alzheimer’s advocacy?
(Sorry, this is a rude joke. Truthfully my disagreement with patent is only medium-strength. I just can’t resist jokes.)
Did you have a substantive response? Or are you just here to deliver meaningless snark?
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.
Instead I will trust that those in the audience that I might care about, can judge your lies and insults correctly.
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.
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)!
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.