Alzheimer’s disease can be reversed in animal models? Study
No synthesized answer yet. Check the discussion below.
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...
- It's plausible that simply supplementing with NMN or NADH would work. 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."
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.
> industry that takes existing drugs that are widely used off-label and patents that off-label use
I wonder why "wide off-lable use" shouldn't be considered prior art?
Companies can get a METHOD-OF-USE PATENT (MOU) on an old drug for a new INDICATION.
This gives them the exclusive right to LABEL AND MARKET that drug for that indication for a period of time.
I however, doctors can prescribe and pharmacists can substitute generics for the new indication, regardless of the MOU.
For a company to profit off an MOU, they strategically need to create a new FORMULATION. This is a new dose or delivery mechanism (extended release, topical, etc). A new formulation can be protected with conventional patents that go beyond an MOU.
With an MOU + patent on a new formulation, the company has a brand where they are the only ones allowed to make the new formulation and the only ones with a product approved to be marketed for the new indication.
Getting FDA approval for the new brand is not the main hurdle for the company. To get insurers to pay the premium they want over the cost of existing treatment options, they have to show it’s safer or more effective than those existing options. Otherwise insurance will block it.
In principle, this means that repurposing should only enable companies to profitably repurpose off patent off label applications if they can provide a real patient benefit.
Whether this is the best or most efficient way to promote this kind of innovation, or whether it works as well in practice as it would seem in theory, is a separate question.
Why?
> 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.
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.
What does it mean if I don’t flush? Is the supplement a dud?
- your supplement is a dud
- you took niacin too often (best to do it once a few days as body adapts quickly)
- you have a gene mutation that prevents you from absorbing enough B3 (common in some schizophrenia cases that can be managed by huge doses of daily B3, like 4-10g)
Oh yeah, I was taking it daily when I stopped flushing. Makes sense.
Is this actually true? I thought it was pretty common for elderly pets
And what about the brains that show plaques, 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?
Nothing. I think it's sometimes in fact called a syndrome, not a disease per se. Since we don't really understand the mechanism of action, it remains more of a diagnosis by exclusion rather than anything else.
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.
As someone who's seen both cancer and Alzheimer's up close, that would be a very easy choice.
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.
He had worked as a professor and after retirement had suffered with AD for years but had stayed "independent" because his wife was high functioning mentally but low functioning physically and formed a good team.
He'd bought long term care insurance so he had the resources to afford both a room at a care home but also personal help from home aides, including my wife. He didn't really know what was going on most of the time but he never got angry or flustered and was always pleasant to deal with.
We had trouble with certain homes having a way they want to do things or requiring things that weren't really necessary, one insisted that he get a pacemaker because he had bradycardia. When he lived with his son between homes probably the most difficult thing was that he got up in the night to use the bathroom and would end up urinating in the wrong place. He got much better care than many residents because people were always coming around to see him and the staff knew that we cared and would advocate for him.
He passed away at 92 and outlived many of the people who knew him at work so he had just a small memorial ceremony. I saw it as an example of healthy aging and talked about it a lot with my wife -- and it made me think about myself and my own fear that my ability to compensate for my schizotaxia may degrade when my brain degrades and I can picture myself becoming really nasty and it gives me all the more incentive to rewrite my habits while I still can.
I've begun taking very small amounts of lithium orotate (5mg), among many other preventative measures.
People with the emotional and compassionate depth of a child are the ones keeping us from allowing people to die with dignity.
The best solution allows it for severe cases, while still investing money in research and spending money for palliative care so it remains an option and not a demand. But that's a tricky line to maintain.
Never something she would have wanted, but you don't really have a choice and dignified death is never given as an option.
https://www.alzint.org/news-events/news/health-tourism-the-l...
That's not a universal law, in fact it is different in other countries, i.e. it is something that can be changed.
No need for lengthy approvals or a drug trial if you’re giving it to yourself. I’d want to go out doing some mfing science.
Is this a problem with the molecule or the dose?
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.
"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."
Getting an aggressive brain cancer when you had early stage alzheimer’s would be tragic.
NAD itself isn’t usually supplemented because it’s broken down by your digestive system. So NAD precursor supplements have been available for a while: NR and NMN specifically. These are the precursors they were talking about.
The actual drug used in this study has a different mechanism of action. It’s not directly available as a supplement, but like the parent commenter discovered you could technically find a chemical supply house to synthesize a tiny quantity of it.
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.
Isn't one of the major complaints is that it works too well? i. e. The emaciated look of those taking it.
https://utsouthwestern.elsevierpure.com/en/publications/deve...
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'?
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.
;)
> 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.
Mouse-heifer’s! <knee slap>
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.
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.)
It's not "House" where you guess something, provide a treatment, watch as things get worse, then change diagnosis in the real world is it?
Right. And I’m arguing that’s more of a fiction than House.
In most cases, waiting for a definitive test can be more harmful than treating when the preponderance of evidence points one way. (In some cases, the test is riskier than the treatment.)
...and also develop one.
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.
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 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-...
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.
I understand the compassion for animals, of course, but not this sentence. Advancing science is not "all for fame or fortune". If it cures people, I can see it. I too would love a world without animal suffering, but I'd also love to not be literally seeing (and I just came back from my parents') my dad slip more and more into nothingness at the hand of this stupid disease.
You had a point until this line.
The purpose is to cure horrible diseases in humans. Fame and fortune come with that because we want people curing horrible diseases. But the core motivation is fighting disease, as evidenced by animal models being used in medical-research systems which do not confer either fame nor fortune on their researchers.
I don’t get this take. Like yes, we aren’t mice, and everything that works in mice won’t work in humans. But loads of things that worked in mice did wind up working in humans, which is why most groundbreaking drugs over the past decades were first explored in mice, which is why we continue to use mouse models.
Sugars and carbs also keep you alive. Please keep your mortality neurosis to yourself.
Just because you made an animal have similar symptoms doesn't mean the animal has Alzheimer's!
I suspect that animal models hinder rather than help science progress because most of the animals models will turn out to be entirely wrong.
Given how I have seen different patients and varying pace of dementia growth - I somehow think Alzheimer’s must have multiple sub families & may appear same but must be behaving differently from their onset.
Which animals besides mice does this cause a full neurological recovery in?
https://www.science.org/content/blog-post/lithium-deficiency...