The authors report that restoring NAD+ balance in the brain -- using a compound called P7C3-A20 -- completely reversed Alzheimer's pathology and recovered cognitive function in two different transgenic mouse models (one amyloid-based, one tau-based). The mice had advanced disease before treatment began.
- There's room for skepticism. As Derek Lowe once wrote: "Alzheimer's therapies have, for the most part, been a cliff over which people push bales of money. There are plenty of good reasons for this: we don't really know what the cause of Alzheimer's is, when you get down to it, and we're the only animal that we know of that gets it. Mouse models of the disease would be extremely useful – you wouldn't even have to know what the problem was to do some sort of phenotypic screen – but the transgenic mice used for these experiments clearly don't recapitulate the human disease. The hope for the last 25 years or so has been that they'd be close enough to get somewhere, but look where we are."
- If the drug's mechanism of action has been correctly assigned, it's very plausible that simply supplementing with NMN, NR, or NADH would work equally well. The authors caution against this on, IMO, extremely shaky and unjustified grounds. "Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer."
There are numerous chemical supply companies that will list chemicals like this “for sale”. They might not have it in stock but they hope they’ll get your search traffic and be able to synthesize it if you place an order.
If you look at the amounts, they’re tiny. I don’t know the doses that would be used in humans but typically ordering from chemical supply shops would be economically infeasible for just about any drug. These are meant for one-off studies and experiments, not ongoing human use.
There have been a growing number of online groups arranging to do group buys of synthesized experimental drugs based on studies. I’ve followed a few of them and the results range from people losing their money, receiving product that is too contaminated to use, or in some cases they go to great lengths to verify the chemical but then discover it doesn’t do what the original study promised it would do. In some of the more horrifying cases I’ve seen forum posts from people reporting long lasting chest pains from one chemical, and another chemical was sending people into psychosis. So if (when) these chemicals start appearing on group buy sites I suggest ignoring it until more research is done. Making yourself into a lab rat is not a good idea.
> If you look at the amounts, they’re tiny. I don’t know the doses that would be used in humans but typically ordering from chemical supply shops would be economically infeasible for just about any drug. These are meant for one-off studies and experiments, not ongoing human use
I didn't get the impression that the person above was suggesting actually buying it here, but rather just pointing out that if it does prove effective in human trials, it's going to become cheaply and easily available since it's already possible to order online for research.
There appears to be some danger in using NAD+ without the supervision of an experienced physician.
"Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer."
There have been a growing number of online groups arranging to do group buys of synthesized experimental drugs based on studies...
There's also a good number of cases of people getting exactly what they ordered. There's been a thriving market for Retatrutide, ozempic's more powerful younger brother, for years despite it not being approved yet.
Also, people with Alzheimer's don't have the luxury of being able to wait 20 years for it to be approved.
I was actually researching this yesterday for a groupbuy, the synth is chromatography-free which means gram scale production is possible with much less cost than expected .
And there's room for thinking there's water in the ocean. We have no idea whether this would work at all or how it would work at all in humans. We have one experiment in mice, which as you say can't have Alzheimer's.
This is a nice step, like developments in fusion energy. That's part of research, and let's hope and investigate it, but it's absurd to think about it as anything but a science project right now.
Sadly, it's worse. We don't have one experiment that works in mice: we have dozens, if not hundreds. We've cured "Alzheimer's in mice" many times over. The treatments never work in humans, because it's not the same disease. We don't know the root cause of the human disease and so we can't model it accurately in mice.
And the author of the paper has disclosed that they have patent on the drug being tested. Let's see if the results can be reproduced by others. Then let's see how it tests with humans.
Aren't "steps" toward fusion energy a little fake though? IIUC fusion research is a front for nuclear testing, so there's a vested interest in showing "progress" to greenwash the gargantuan spend on nuclear weapons.
EDIT referring to the need for fusion and plasma research for modeling warheads in the absence of full tests.
> Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer.
As someone who's seen both cancer and Alzheimer's up close, that would be a very easy choice.
Except that time of death comes on average many years later for Alzheimer's than cancer. In the same thought, better die from heart attack instantly but unfortunately much earlier, which would be devastating for the relatives.
> Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer.
Does this mean that people are having to trade Alzheimer in exchange for high risk of cancer? Or does this mean that we need better precursors that don't require that trade off?
There's no good evidence that supplementation with NMN, NR, etc. increases the risk of cancer in healthy people. There's some speculation that it might be risky for people with cancer to take those supplements, but the picture is far from clear. Some papers even suggest that they can be beneficial. (e.g., https://pmc.ncbi.nlm.nih.gov/articles/PMC10177531/ )
In terms of risk-benefit analysis, if this stuff actually cures Alzheimer's, then even a 10x increased risk of cancer (all types) is acceptable, as Alzheimer's is frequently a fate worse than death whereas cancer can be managed whilst keeping your personality and sanity intact. In reality, the increased risk of cancer from something like NMN is perhaps 1.005x. To all appearances, totally negligible.
The problem, for Pieper, is that NMN/NR/NADH are ubiquitous and cost pennies per dose. So, if they work (big if), this new research is unmonetizable. The team leads would win a Nobel Prize, but Big Pharma gigabucks are out of the question. Let's see what happens.
> Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. The pharmacological approach in this study, however, uses a pharmacologic agent (P7C3-A20) that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels.
I think it means one should read the very next sentence:
> Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. The pharmacological approach in this study, however, uses a pharmacologic agent (P7C3-A20) that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels.
There’s a lot of umbrella diagnoses that would benefit from more specific diagnostics first. What we call Alzheimer’s is probably actually caused by number of different causes depending on the person. This is true of a lot of things in medicine that get grouped together. That’s why testing a drug in mouse models with all the same characteristics sometimes works but fails to translate into humans who have more variety amongst each other.
The same is true of many diagnoses like pneumonia, cancer, alopecia, essential tremor: there’s multiple different groups that would benefit from different things, and if we had better ways to identify the groups, we’d give them what works for them instead of wasting their time with the wrong treatment. As an example, antibiotics won’t work for viral pneumonia and in addition to wasting the patient’s time, actually harm your microbiome. If you had a perfect way to know which is which, you’d always get the right treatment.
I recall a University of Washington (I think it was) where they were saying they had found Schizophrenia to be a bucket diagnosis, and had discovered that multiple sets of genes were working together in specific testable ways such that there were >4 sub types of Schizophrenia each with its own set of symptoms, and ability to respond to different medications.
The researcher did a follow-up study to confirm their thesis, but I've never seen anyone else follow up on those studies (family with Schizophrenia makes me acutely aware of developments in that field)
Many disease labels just mean inflammation-of-a tissue / organ.
Worth noting that some viral inflections of the respiratory tract will have a bacterial secondary, where an either commensal bacteria has over proliferated or a pathogenic bacteria has started to get a hold, and treating the bacterial secondary can help the patient better fight the viral primary.
It's quite terrible how the medical "debugging" works or rather doesn't. You run a bunch (at best) of tests then pick the most probable diagnosis and that's about it for 99.9% of cases. And then in a review you measure that the world's best performing doctor hit 45% accuracy whereas an average one hits ~33%.
As someone who has been debugging their own chronic illnesses for the past ten years (and doing better than my doctors), I wouldn’t consider the medical diagnostic process to be “debugging” at all. And that is exactly the problem. Doctors seem to be stuck thinking like bureaucrats following probabilistic flowcharts, and they’re incapable of actually thinking about a problem and debugging it.
The behavior seems to be so deeply ingrained in every single doctor I’ve seen that it seems impossible to change. I suspect they must have this drilled into them in school and residency, then it seems like every decision is constrained by insurance requirements. As far as I can tell, the situation is hopeless.
They mean the fake Alzheimer's they induce by injecting poison into 3 month old animals or which develops in mice genetically engineered to have diseases that aren't Alzheimer's but are somewhat similar to Alzheimer's in some ways, not the kind where you wait 70 years for a human to develop which they don't even really understand what causes it.
I used to work with a guy who had been a scientist at a large pharma company (we were both working at a small biotech start-up at the time).
He told me an interesting story... basically, scientists at his company would get an extra year-end bonus if they had worked on a drug candidate that made it past animal studies and into human (clinical) trials.
He told me that one way to 'consistently' get the extra bonus was to work on candidate drugs for neurological diseases (e.g., Alzheimer's, etc.) because ... the animal models for those diseases were (generally) dog shit, so it was easy to find a drug that 'cured' whatever happened to be your neurological disease of interest in mice/rats/etc.
Then you get your bonus and the drug fails in humans.
A key challenge with Alzheimer’s is there is no good mouse model for the disease. While some approximate the phenotype, it’s not clear that the disease model as commonly studied in mice matches well with mechanisms of the human disease. There’s some thinking in the field that this could be a key reason why so many treatments have appeared very promising in mice and haven’t panned out in humans.
When enough words, framing, and unstated important premises are omitted, it crosses over from the realm of incomplete or misleading into plain outright lying in my worldview.
They claim "Reverses advanced AD in mice." What they did is reverse symptoms in genetic models.
They claim to "Restore NAD+ homeostasis," ignoring that NAD might not even be causally related to Alzheimer’s, just a side effect. It’s like saying we cured a house fire because we efficiently removed the ashes after the fire. It’s the Tau thing all over again.
The claim: "Conservative molecular signatures" when in reality, 5xFAD mice are poor predictors of human clinical success to such a degree that it’s statistically more common for mice studies to NOT transfer to human biology than to do so.
They also make unsupported claims like "Safer than NAD+ precursors (supplements)," when this is a pre-clinical assumption. No human toxicity trials are mentioned in this context, and there are always MASSIVE differences when switching to real human studies. It might be correct, but there’s no basis to say that based on this study.
Also, the senior author owns the company. The paper has the hallmarks of a "pitch deck" for the drug.
In short, it seems to me that the claim of "Full Neurological Recovery" is misleading to patients. It fails to prove that fixing NAD+ in humans will stop the disease, only that it works in mice engineered to have the disease, and only by assuming that their specific measure is a 1-to-1 with the clinical presentation of the disease. The results are likely the "best case scenario" presented to support the commercialization of P7C3-A20.
Here is the COMMON SENSE question peer-reviews should have asked.
Is low NAD+ the fire, or just the ashes?
Why should we believe this works in humans when the last 500 'cures' in 5xFAD mice failed?
Are you regrowing a brain, or just cleaning up a dirty one?
How does one molecule fix five unconnected problems simultaneously? The Context: The drug fixed inflammation, blood-brain barrier, amyloid/tau (protein folding), and memory (neuronal signaling). Drugs rarely hit four distinct biological systems with 100% success....
Where is the toxicology report that proves 'safer than supplements'?
You're asking good questions, but it's unreasonable to expect one paper to answer all of them. Probably the article should have emphasized more strongly that mouse models are imperfect, but they do show efficacy in two different mouse models, which counts for something.
> It fails to prove that fixing NAD+ in humans will stop the disease, only that it works in mice engineered to have the disease
This in particular is just not possible without clinical trials in humans. But you can't have a clinical trial without evidence of efficiency, so you need to start with mouse models, even if they are imperfect. Sadly we don't know if any of the existing mouse models are any good, but it's the best we've got.
They put themselves in the position of having to answer these questions given their claims. I’m not suggesting they should figure out everything about everything, but given the over the top claims made, these are the least they should be able to answer.
Please... people, do not get your hopes up over this one PR pump piece released on Christmas Day. This is not a legit study. (It might, perhaps, somehow, still be correct, perhaps... even broken clocks are right twice a day... but it's still not a legit study.)
Well, NAD+ kinda has the potential to fix multiple things at once if those things are caused by energetic imbalance/deficit. Re-balancing NAD+ could just fix multiple failing systems that were running low on energy and not doing their job properly as a consequence.
Readit News
Three comments:
- You can actually buy the drug here: https://focusbiomolecules.com/p7c3-a20-nampt-activator-prone... It's a simple small molecule. If this stuff works, expect it to be everywhere within just a couple of years.
- There's room for skepticism. As Derek Lowe once wrote: "Alzheimer's therapies have, for the most part, been a cliff over which people push bales of money. There are plenty of good reasons for this: we don't really know what the cause of Alzheimer's is, when you get down to it, and we're the only animal that we know of that gets it. Mouse models of the disease would be extremely useful – you wouldn't even have to know what the problem was to do some sort of phenotypic screen – but the transgenic mice used for these experiments clearly don't recapitulate the human disease. The hope for the last 25 years or so has been that they'd be close enough to get somewhere, but look where we are."
> https://www.science.org/content/blog-post/just-how-worthless...
- If the drug's mechanism of action has been correctly assigned, it's very plausible that simply supplementing with NMN, NR, or NADH would work equally well. The authors caution against this on, IMO, extremely shaky and unjustified grounds. "Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer."
There are numerous chemical supply companies that will list chemicals like this “for sale”. They might not have it in stock but they hope they’ll get your search traffic and be able to synthesize it if you place an order.
If you look at the amounts, they’re tiny. I don’t know the doses that would be used in humans but typically ordering from chemical supply shops would be economically infeasible for just about any drug. These are meant for one-off studies and experiments, not ongoing human use.
There have been a growing number of online groups arranging to do group buys of synthesized experimental drugs based on studies. I’ve followed a few of them and the results range from people losing their money, receiving product that is too contaminated to use, or in some cases they go to great lengths to verify the chemical but then discover it doesn’t do what the original study promised it would do. In some of the more horrifying cases I’ve seen forum posts from people reporting long lasting chest pains from one chemical, and another chemical was sending people into psychosis. So if (when) these chemicals start appearing on group buy sites I suggest ignoring it until more research is done. Making yourself into a lab rat is not a good idea.
I didn't get the impression that the person above was suggesting actually buying it here, but rather just pointing out that if it does prove effective in human trials, it's going to become cheaply and easily available since it's already possible to order online for research.
"Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer."
There's also a good number of cases of people getting exactly what they ordered. There's been a thriving market for Retatrutide, ozempic's more powerful younger brother, for years despite it not being approved yet.
Also, people with Alzheimer's don't have the luxury of being able to wait 20 years for it to be approved.
https://utsouthwestern.elsevierpure.com/en/publications/deve...
And there's room for thinking there's water in the ocean. We have no idea whether this would work at all or how it would work at all in humans. We have one experiment in mice, which as you say can't have Alzheimer's.
This is a nice step, like developments in fusion energy. That's part of research, and let's hope and investigate it, but it's absurd to think about it as anything but a science project right now.
EDIT referring to the need for fusion and plasma research for modeling warheads in the absence of full tests.
As someone who's seen both cancer and Alzheimer's up close, that would be a very easy choice.
Is this a problem with the molecule or the dose?
there are studies about this compound from a decade ago, kinda doubt it's going to be a breakthrough at this point
Is this actually true? I thought it was pretty common for elderly pets
Does this mean that people are having to trade Alzheimer in exchange for high risk of cancer? Or does this mean that we need better precursors that don't require that trade off?
In terms of risk-benefit analysis, if this stuff actually cures Alzheimer's, then even a 10x increased risk of cancer (all types) is acceptable, as Alzheimer's is frequently a fate worse than death whereas cancer can be managed whilst keeping your personality and sanity intact. In reality, the increased risk of cancer from something like NMN is perhaps 1.005x. To all appearances, totally negligible.
The problem, for Pieper, is that NMN/NR/NADH are ubiquitous and cost pennies per dose. So, if they work (big if), this new research is unmonetizable. The team leads would win a Nobel Prize, but Big Pharma gigabucks are out of the question. Let's see what happens.
> Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. The pharmacological approach in this study, however, uses a pharmacologic agent (P7C3-A20) that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels.
> Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. The pharmacological approach in this study, however, uses a pharmacologic agent (P7C3-A20) that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels.
Dead Comment
The same is true of many diagnoses like pneumonia, cancer, alopecia, essential tremor: there’s multiple different groups that would benefit from different things, and if we had better ways to identify the groups, we’d give them what works for them instead of wasting their time with the wrong treatment. As an example, antibiotics won’t work for viral pneumonia and in addition to wasting the patient’s time, actually harm your microbiome. If you had a perfect way to know which is which, you’d always get the right treatment.
Precision medicine takes this even further.
The researcher did a follow-up study to confirm their thesis, but I've never seen anyone else follow up on those studies (family with Schizophrenia makes me acutely aware of developments in that field)
https://source.washu.edu/2014/09/schizophrenia-not-a-single-...
oh, would you look at that - a newer study https://biology.ucdavis.edu/news/discovery-hints-genetic-bas...
Many disease labels just mean inflammation-of-a tissue / organ.
Worth noting that some viral inflections of the respiratory tract will have a bacterial secondary, where an either commensal bacteria has over proliferated or a pathogenic bacteria has started to get a hold, and treating the bacterial secondary can help the patient better fight the viral primary.
The behavior seems to be so deeply ingrained in every single doctor I’ve seen that it seems impossible to change. I suspect they must have this drilled into them in school and residency, then it seems like every decision is constrained by insurance requirements. As far as I can tell, the situation is hopeless.
Not necessarily. Often, treatment and testing can be done in parallel.
In many cases, the treatment is also a test. Every time you apply topical antibiotics to a cut, you’re testing for antibiotic resistance.
Merry Christmas!
I used to work with a guy who had been a scientist at a large pharma company (we were both working at a small biotech start-up at the time).
He told me an interesting story... basically, scientists at his company would get an extra year-end bonus if they had worked on a drug candidate that made it past animal studies and into human (clinical) trials.
He told me that one way to 'consistently' get the extra bonus was to work on candidate drugs for neurological diseases (e.g., Alzheimer's, etc.) because ... the animal models for those diseases were (generally) dog shit, so it was easy to find a drug that 'cured' whatever happened to be your neurological disease of interest in mice/rats/etc.
Then you get your bonus and the drug fails in humans.
Lather, rinse, repeat.
Let's hope the cure can be transfered to humans, but I think the chances are extremly low.
When enough words, framing, and unstated important premises are omitted, it crosses over from the realm of incomplete or misleading into plain outright lying in my worldview.
They claim "Reverses advanced AD in mice." What they did is reverse symptoms in genetic models.
They claim to "Restore NAD+ homeostasis," ignoring that NAD might not even be causally related to Alzheimer’s, just a side effect. It’s like saying we cured a house fire because we efficiently removed the ashes after the fire. It’s the Tau thing all over again.
The claim: "Conservative molecular signatures" when in reality, 5xFAD mice are poor predictors of human clinical success to such a degree that it’s statistically more common for mice studies to NOT transfer to human biology than to do so.
They also make unsupported claims like "Safer than NAD+ precursors (supplements)," when this is a pre-clinical assumption. No human toxicity trials are mentioned in this context, and there are always MASSIVE differences when switching to real human studies. It might be correct, but there’s no basis to say that based on this study.
Also, the senior author owns the company. The paper has the hallmarks of a "pitch deck" for the drug.
In short, it seems to me that the claim of "Full Neurological Recovery" is misleading to patients. It fails to prove that fixing NAD+ in humans will stop the disease, only that it works in mice engineered to have the disease, and only by assuming that their specific measure is a 1-to-1 with the clinical presentation of the disease. The results are likely the "best case scenario" presented to support the commercialization of P7C3-A20.
Here is the COMMON SENSE question peer-reviews should have asked. Is low NAD+ the fire, or just the ashes?
Why should we believe this works in humans when the last 500 'cures' in 5xFAD mice failed?
Are you regrowing a brain, or just cleaning up a dirty one?
How does one molecule fix five unconnected problems simultaneously? The Context: The drug fixed inflammation, blood-brain barrier, amyloid/tau (protein folding), and memory (neuronal signaling). Drugs rarely hit four distinct biological systems with 100% success....
Where is the toxicology report that proves 'safer than supplements'?
> It fails to prove that fixing NAD+ in humans will stop the disease, only that it works in mice engineered to have the disease
This in particular is just not possible without clinical trials in humans. But you can't have a clinical trial without evidence of efficiency, so you need to start with mouse models, even if they are imperfect. Sadly we don't know if any of the existing mouse models are any good, but it's the best we've got.
Unfortunately, the moment I saw reference to NAD+ I started looking for this. Thank you.
Please... people, do not get your hopes up over this one PR pump piece released on Christmas Day. This is not a legit study. (It might, perhaps, somehow, still be correct, perhaps... even broken clocks are right twice a day... but it's still not a legit study.)
Broken clocks can be broken in ways that causes them to be up to and including never correct.
;)
https://www.science.org/content/blog-post/lithium-deficiency...