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."
> 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.
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.
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.
Is this the same NAD+ that’s prescribed by longevity / hormone clinics?
Edit: after some googling, sounds like NAD+ (which you can get from real doctors) is the “building blocks” similar to how protein is the building blocks for muscle, while the experimental compound changes/enhances how the building blocks are used inside your cells.
Alzheimer's is, by definition, dementia with associated amyloid plaques in the brain. Since you can't detect the plaques without cutting into the brain, the diagnosis is normally given based on symptoms of dementia (significant loss of memory or other cognitive functions) without other clear reasons (no evidence of vascular events, head trauma, brain tumors or other neurological diseases etc).
> 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.
Could explain how a compound that's already on the market and has been patented for (some) medical use at least once in 2015 (expiring 2035) might make a good case for "Big Pharma gigabucks"? I thought one reason for a lack of research into "repurposablity" of existing small molecule drugs is the fact that new applications cannot be independently patented?
You absolutely can patent existing drugs. There's a whole scummy pharma industry that takes existing drugs that are widely used off-label and patents that off-label use.
Furthermore, we don't even know whether NAD precursor supplementation works. They raise intracellular NAD+ levels, but unclear whether they raise intercellular NAD+, which is what really matters. There are also those that say NAD+ recycling matters more than we think, and precursors don't address that.
> 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.
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'?
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.)
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.
Anytime I see headlines like these, I think of the countless animals tortured to death. The sheer level of suffering, all for this Frankenstein nonsense. 90–95% of drugs that appear safe and effective in animal tests ultimately fail in human trials. They mention mice, but there are likely other animals involved, like dogs. Animals deliberately bred with crippling diseases, all for fame and fortune.
More than 110 million animals are killed in the United States each year in experiments. I'd rather just accept Alzheimer's than be complicit in this evil.
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."
As someone who's seen both cancer and Alzheimer's up close, that would be a very easy choice.
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.
there are studies about this compound from a decade ago, kinda doubt it's going to be a breakthrough at this point
Edit: after some googling, sounds like NAD+ (which you can get from real doctors) is the “building blocks” similar to how protein is the building blocks for muscle, while the experimental compound changes/enhances how the building blocks are used inside your cells.
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.
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.
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'?
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.)
Which animals besides mice does this cause a full neurological recovery in?
Let's hope the cure can be transfered to humans, but I think the chances are extremly low.
https://www.science.org/content/blog-post/lithium-deficiency...
More than 110 million animals are killed in the United States each year in experiments. I'd rather just accept Alzheimer's than be complicit in this evil.