5 ms·

The authors report that restoring NAD+ balance in the brain -- using a compound called P7C3-A20 -- completely reversed Alzheimer's pathology and recovered cogni

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. Three comments: - You can actually buy the drug here: https://focusbiomolecules.com/p7c3-a20-nampt-activator-proneurogenic-agent/ 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-are-standard-alzheimer-s-models 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."

bossyTeacher 10mo ago
> 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?
- juujian 10mo ago
  It's a quality of life vs years left calculation you have to make on a case by case basis.
  - mmooss 10mo ago
    You can't make calculations without data, and in this case you have none: we have no idea of the effects on humans.
- shawnz 10mo ago
  Keep reading: > 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.
- luma 10mo ago
  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.
- A_D_E_P_T 10mo ago
  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/ 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.
Palomides 10mo ago
>expect it to be everywhere within just a couple of years. there are studies about this compound from a decade ago, kinda doubt it's going to be a breakthrough at this point
- SoftTalker 10mo ago
  Searching for "P7C3-A20" just now, looks like it's readily available now from multiple sources.
  - cj 10mo ago
    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.
    - andy_ppp 10mo ago
      So you might need some NAD+ precursor like NMN and this compound for it to work in humans because by the time you’re old it’s much harder for your body to make. Was the experiment done in older mice or younger ones that have NAD+ but artificial Alzheimer’s ?
      - JumpCrisscross 10mo ago
        What’s the current state of between NMN, NR and straight-up niacin?
        storus 10mo ago
        NMN and NR are both good but NMN might not be available anymore as some company decided to repurpose it as a drug instead of supplement. Best combo nowadays looks to be liposomal NR with pterostilbene, a sirtuin activator. NR boosts NAD+ (the main electron transporter in mitochondria), pterostilbene activates sirtuin SIRT1 that regulates aging. B2/Riboflavin might be a good idea as well as it is a FADH donor, secondary electron transport carrier especially in nerves/brain. B1 to the mix as every single metabolic reaction needs it and it's depleted by consuming lots of carbs or drinking alcohol, a common western diet. Niacin is less effective in raising NAD+ but the flush can open up veins and flood hard to reach extremities of the body with blood so it's probably good from time to time. Slow B3 seems to be even worse for raising NAD+.
hnlmorg 10mo ago
> and we're the only animal that we know of that gets it. Is this actually true? I thought it was pretty common for elderly pets
- xenospn 10mo ago
  Elderly pets have loss of cognitive function/memory, but I don't think it's the same disease.
  - anonym29 10mo ago
    What's the objective, clearly disambiguated, empirically demonstrable difference between memory loss, dementia, and Alzheimer's?
    - tsimionescu 10mo ago
      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).
      - armadsen 10mo ago
        My understanding is that amyloid plaques can actually be seen with a specialized PET scan now, so it can be more definitively diagnosed in living people.
      - anonym29 10mo ago
        You mentioned amyloid plaques. What about tau tangles? I thought Alzheimer's required both. If someone (or some dog, for that matter) has amyloid plaques but no tau tangles, is that Alzheimer's? If they have tau tangles but no amyloid plaques, what is it? And what about the brains that show amyloid plaques, tau tangles, and Lewy bodies? Or plaques plus vascular lesions? At autopsy, most elderly brains show mixed pathology. Does that person have Alzheimer's plus Lewy body dementia plus vascular dementia? Three diseases? Or one brain failing in multiple correlated ways that we've artificially carved into separate categories? It sounds like we have at least five different pathological markers that correlate with cognitive decline, often co-occurring, with inconsistent symptom mapping. What makes 'Alzheimer's' a disease rather than a region we've named in a high-dimensional space we don't really understand all that well?
mmooss 10mo ago
> There's room for skepticism. 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.
- thisislife2 10mo ago
  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.
  - deleted 10mo ago
    [deleted]
- reissbaker 10mo ago
  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.
  - everdrive 10mo ago
    I totally get that people are not mice, however animals studies have been useful for all sorts of diseases. Are they really uniquely bad for Alzheimer's?
    - adinb 10mo ago
      No. I believe the problem is with our artificial models of Alzheimer’s in mice.
    - greygoo222 10mo ago
scarmig 10mo ago
> 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.
- kingofmen 10mo ago
  Uh... which one? Choice is not obvious to me, and I think it would depend on the type of cancer.
  - ramencentral 10mo ago
    Cancer is better than Alzheimer’s. There is no comparison. I wouldn’t wish Alzheimer’s or dementia on my worst enemy.
  - idiotsecant 10mo ago
    Cancer times a million
  - scarmig 10mo ago
    Cancer. The worst types of it have the advantage of killing quickly. Alzheimer's destroys the self, and you survive a long time with it, leading to much more suffering, both to you (to the extent you continue to exist) and to your family.
    - deepspace 10mo ago
      I have a different perspective. The worst types of cancer kill slowly and cause agonizing suffering. Alzheimer's leads to negative outcomes for your caregivers, but by many accounts many affected individuals do not suffer all that much, if at all, due to their lack of awareness.
  - shepardrtc 10mo ago
    From multiple personal experiences, including both of my parents, dementia is a slow, horrible death where you are robbed of your dignity and end up dragging all of your relatives through a very long, very torturous hell. You will be drooling, pissing, and shitting yourself, all while slowly reverting back to a low IQ childhood mentality where you're very likely to have outbursts and verbally or physically attack the people around you. Your loved ones will be tormented, and if you don't have loved ones then if you're lucky you'll be tossed into a room and forgotten about by underpaid, overworked staff at some run-down nursing home. If you're not lucky you'll be laying in a gutter on the street until you die.
Aurornis 10mo ago
> - You can actually buy the drug here: https://focusbiomolecules.com/p7c3-a20-nampt-activator-prone 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 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.
- chasil 10mo ago
  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."
  - digitaltrees 10mo ago
    Most people with Alzheimer’s are older and would probably trade having their cognitive abilities back even with increased risk of cancer
    - timr 10mo ago
      Depends entirely on the stage of the disease and the aggressiveness of the cancer! Getting an aggressive brain cancer when you had early stage Alzheimer’s [1] would be tragic. The tradeoff would be years of life. For the record, I have no idea what the actual risk tradeoff is, but the point of regulation is that nobody does. You can’t have informed consent when you can’t be informed. [1] Aside: Alzheimer’s is relatively early stage, as dementias go. It’s frequently diagnosed by onset in younger people.

bossyTeacher 10mo ago

> 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?

juujian 10mo ago
It's a quality of life vs years left calculation you have to make on a case by case basis.
- mmooss 10mo ago
  You can't make calculations without data, and in this case you have none: we have no idea of the effects on humans.
shawnz 10mo ago
Keep reading: > 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.
luma 10mo ago
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.
A_D_E_P_T 10mo ago
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/ 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.

Palomides 10mo ago

>expect it to be everywhere within just a couple of years. there are studies about this compound from a decade ago, kinda doubt it's going to be a breakthrough at this point

SoftTalker 10mo ago
Searching for "P7C3-A20" just now, looks like it's readily available now from multiple sources.
- cj 10mo ago
  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.
  - andy_ppp 10mo ago
    So you might need some NAD+ precursor like NMN and this compound for it to work in humans because by the time you’re old it’s much harder for your body to make. Was the experiment done in older mice or younger ones that have NAD+ but artificial Alzheimer’s ?
    - JumpCrisscross 10mo ago
      What’s the current state of between NMN, NR and straight-up niacin?
      - storus 10mo ago
        NMN and NR are both good but NMN might not be available anymore as some company decided to repurpose it as a drug instead of supplement. Best combo nowadays looks to be liposomal NR with pterostilbene, a sirtuin activator. NR boosts NAD+ (the main electron transporter in mitochondria), pterostilbene activates sirtuin SIRT1 that regulates aging. B2/Riboflavin might be a good idea as well as it is a FADH donor, secondary electron transport carrier especially in nerves/brain. B1 to the mix as every single metabolic reaction needs it and it's depleted by consuming lots of carbs or drinking alcohol, a common western diet. Niacin is less effective in raising NAD+ but the flush can open up veins and flood hard to reach extremities of the body with blood so it's probably good from time to time. Slow B3 seems to be even worse for raising NAD+.

hnlmorg 10mo ago

> and we're the only animal that we know of that gets it. Is this actually true? I thought it was pretty common for elderly pets

xenospn 10mo ago
Elderly pets have loss of cognitive function/memory, but I don't think it's the same disease.
- anonym29 10mo ago
  What's the objective, clearly disambiguated, empirically demonstrable difference between memory loss, dementia, and Alzheimer's?
  - tsimionescu 10mo ago
    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).
    - armadsen 10mo ago
      My understanding is that amyloid plaques can actually be seen with a specialized PET scan now, so it can be more definitively diagnosed in living people.
    - anonym29 10mo ago
      You mentioned amyloid plaques. What about tau tangles? I thought Alzheimer's required both. If someone (or some dog, for that matter) has amyloid plaques but no tau tangles, is that Alzheimer's? If they have tau tangles but no amyloid plaques, what is it? And what about the brains that show amyloid plaques, tau tangles, and Lewy bodies? Or plaques plus vascular lesions? At autopsy, most elderly brains show mixed pathology. Does that person have Alzheimer's plus Lewy body dementia plus vascular dementia? Three diseases? Or one brain failing in multiple correlated ways that we've artificially carved into separate categories? It sounds like we have at least five different pathological markers that correlate with cognitive decline, often co-occurring, with inconsistent symptom mapping. What makes 'Alzheimer's' a disease rather than a region we've named in a high-dimensional space we don't really understand all that well?

mmooss 10mo ago

> There's room for skepticism. 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.

thisislife2 10mo ago
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.
- deleted 10mo ago
  [deleted]
reissbaker 10mo ago
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.
- everdrive 10mo ago
  I totally get that people are not mice, however animals studies have been useful for all sorts of diseases. Are they really uniquely bad for Alzheimer's?
  - adinb 10mo ago
    No. I believe the problem is with our artificial models of Alzheimer’s in mice.
  - greygoo222 10mo ago

scarmig 10mo ago

> 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.

kingofmen 10mo ago
Uh... which one? Choice is not obvious to me, and I think it would depend on the type of cancer.
- ramencentral 10mo ago
  Cancer is better than Alzheimer’s. There is no comparison. I wouldn’t wish Alzheimer’s or dementia on my worst enemy.
- idiotsecant 10mo ago
  Cancer times a million
- scarmig 10mo ago
  Cancer. The worst types of it have the advantage of killing quickly. Alzheimer's destroys the self, and you survive a long time with it, leading to much more suffering, both to you (to the extent you continue to exist) and to your family.
  - deepspace 10mo ago
    I have a different perspective. The worst types of cancer kill slowly and cause agonizing suffering. Alzheimer's leads to negative outcomes for your caregivers, but by many accounts many affected individuals do not suffer all that much, if at all, due to their lack of awareness.
- shepardrtc 10mo ago
  From multiple personal experiences, including both of my parents, dementia is a slow, horrible death where you are robbed of your dignity and end up dragging all of your relatives through a very long, very torturous hell. You will be drooling, pissing, and shitting yourself, all while slowly reverting back to a low IQ childhood mentality where you're very likely to have outbursts and verbally or physically attack the people around you. Your loved ones will be tormented, and if you don't have loved ones then if you're lucky you'll be tossed into a room and forgotten about by underpaid, overworked staff at some run-down nursing home. If you're not lucky you'll be laying in a gutter on the street until you die.

Aurornis 10mo ago

> - You can actually buy the drug here: https://focusbiomolecules.com/p7c3-a20-nampt-activator-prone 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 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.

chasil 10mo ago
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."
- digitaltrees 10mo ago
  Most people with Alzheimer’s are older and would probably trade having their cognitive abilities back even with increased risk of cancer
  - timr 10mo ago
    Depends entirely on the stage of the disease and the aggressiveness of the cancer! Getting an aggressive brain cancer when you had early stage Alzheimer’s [1] would be tragic. The tradeoff would be years of life. For the record, I have no idea what the actual risk tradeoff is, but the point of regulation is that nobody does. You can’t have informed consent when you can’t be informed. [1] Aside: Alzheimer’s is relatively early stage, as dementias go. It’s frequently diagnosed by onset in younger people.