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Alzheimer’s disease can be reversed in animal models? Study

487 points by thunderbong

by A_D_E_P_T

6 subcomments

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-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."

by jrpt

4 subcomments

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.
Precision medicine takes this even further.

by 7thpower

1 subcomments

This is great news for mice who have something vaguely similar to Alzheimer’s.

by ltbarcly3

3 subcomments

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.

by ganesh7

0 subcomment

This is eyewatering. My father and grandfather died early due to this condition. Hope for many.

by tbenst

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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.

by jtrn

4 subcomments

This is totally improper reporting of the study.
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'?

by cubefox

0 subcomment

Related: Recently another study on a mouse model had similar effects when using lithium orotate:
https://www.science.org/content/blog-post/lithium-deficiency...

by kinj28

0 subcomment

My cofounders mom had got Alzheimer’s at rather younger age of 60 something. It grew extremely rapid and within 2 years she grew into a vegetative state.
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.

by beckerdo

1 subcomments

It's a useful discovery. The real proof and utility is if what they learned from "mouse-heimer's" can be applied to human Alzheimer's.

by jmward01

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Not my field, but I think a big point here is this isn't purely researching into Amyloid plaques. It is way past time to explore many other possibilities and it is promising to see research in a different direction. This isn't to say Amyloid plaques aren't worthy of research, but when you slam into a wall for a few decades then maybe you should look in different directions now and again.

by briandw

2 subcomments

Boosting NAD has a been the focus of taking NMN supplements. Seems like NMN is a dud for boosting NAD. I wonder if P7C3-A20 can be used instead?

by bilsbie

0 subcomment

GOOD point by my wife, how does this affect those with apoe4 status. And also is there any connection with the recent lithium findings.

by looneysquash

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"Animals" suggests more than one kind of animal.
Which animals besides mice does this cause a full neurological recovery in?

by londons_explore

0 subcomment

I really don't see how you can make an animal model of something you don't fully understand in humans.
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.

by 1970-01-01

1 subcomments

Yet another "in mice" breakthrough. The cerebral cortex of a mouse has around 8–14 million neurons while in those humans there are more than 10–15 billion. So scale this outcome by literally 1000x more neurons and wake me when the chimps are remembering how to hold a long conversation.

by Adrian_Vanessa

0 subcomment

[dead]

by xvxvx

5 subcomments

[flagged]

by mbrochh

1 subcomments

Usual PSA: Don't wait for a cure for Alzheimers. Work towards not getting it in the first place. Alzheimers is "brain diabetes". You get it from consuming sugars and carbs. It can be easily avoided.