"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.
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.
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
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.
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, 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.
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.
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.
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.
> 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.
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.
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.
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 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.
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 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.
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)
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.
34 comments
[ 2.7 ms ] story [ 53.0 ms ] thread"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.
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.
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.
Right?
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.
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 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!
That’s wild.
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.
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)!
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.
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'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.
I really wish the news sites would get it correctly from time to time, this is misleading as hell.
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.
We're going to be ruled be a race of super healthy, immortal, super intelligent lab mice.
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)
https://pmc.ncbi.nlm.nih.gov/articles/PMC10671257/
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.
is a bit of a clickbait stretch. Treatments in humans targeting amyloid have failed to have much effect on Alzheimer's.