The title is a bit link-bait. It should really be "Disrupting circadian rhythms of plaque-clearing brain cells is associated with Alzheimer's"
> He found that too much of YKL-40, which is linked to Alzheimer’s risk in humans, leads to amyloid build-up, an accumulation that is a hallmark of the neurodegenerative disease.
There are countless studies that highlight how genetics or lifestyle and other factors that result in a reduction of estrogen signaling are associated with Alzheimer's. Estrogen, primarily activated at night decreases the expression of the YKL-40 gene. All of the known interventions, from vitamin D, Mg, to gut, choline, etc all can improve estrogen signaling, decreasing YKL-40 gene. One can end up with Alzheimer's from many different routes so interventions depend on the person.
If there was a pill on the market today that would only increase the plaque-clearing all this really does is move the needle, they still have reduced estrogen signaling and the next weakest part of the system would fail such as from animpaired immune system and they will probably die of pneumonia.
But we could back up and say what is the most common cause of the global reduced estrogen signaling? Often increased oxy-androgens (which increase as we age), so for example 11-ketotestosterone (11-KT) which can't convert to its estrogen form results in upregulates HSD17B2. Why do we have so much inflammation causing increased oxy-androgens from the adrenals? Senescence cells releasing inflammatory factors SASP. More time more time spent on repair resulting in identity loss and mesenchymal drift. All a fancy way of saying we get older and will probably die from whatever weakest part of the system we have genetically. Fix one thing and something else breaks instead.
And for those that want to bring in the most well known genetic mutation APOE e4: APOE e4/e4 has elevated choline demands hindering estrogen signaling as well as raising HDL and lowering LDL. Low estrogen influences Cholesteryl Ester Transfer Protein, raising HDL and lowers LDL beyond what e4/e4 does by itself. With less choline and less phosphatidylcholine, it decreases GLUT1 transporters reducing glucose entering the brain. All of the above leads to an escalating amyloid plaque burden. Then reduced deep sleep and the glymphatic system cleaning is reduced too and you have Alzheimer's.
The above was just from memory probably had an error, but the point is Alzheimer's is not "simple" like this article pretends.
Your general point about how complicated it is is well taken, but a theoretical pill that stages off Alzheimer's at the expense of immunocompromise and means you die of pneumonia with your faculties mostly intact seems like a huge win. I don't think we're bothered about Alzheimer's as a proxy for old age, I think it's because dementia is a uniquely horrible disease.
I am not saying that if there was a pill on the market today that would increase plaque-clearing there wouldn't still be dementia, simply that they would probably then die from pneumonia.
One needs to also dive into neurogenesis. Elevated HPA Axis activation which brought us the oxy-androgens also gives use higher cortisol and lower α-MSH which promote neurogenesis. This elevated cortisol is one of the classic hallmarks of Alzheimer's. Estrogen signaling is also an important part of neurodevelopment. So someone with Alzheimer's usually has low α-MSH and low estrogen signaling and overall reduced neurodevelopment. Need to fix these to prevent dementia.
The various stuff that has been found to reduces dementia also improve estrogen signaling. Estrogens are an incredibly old hormone used in regulating a ton of basic cell function. Keep ERa functioning well and you get not only better amyloid plaque clearance, but healthier DNA repair, immune system, etc and better neurogenesis. A lot of stuff that improves longevity ultimately just keeps this going.
There is a Alzheimer's Choline camp which is where we know that Choline supplements is associated with improved Alzheimer's. With low estrogen signaling you have lower N-methyltransferase so less Choline in the body as it is how the body makes it. Less Choline, less SAM via BHMT, less SAM, less clearance of 2-OHE1, less ERa activation, and ... less choline in a loop. Supplement with Choline and it helps not only with the APOE e4 which consumes more Choline, but undoes this is what this theory is about.
As we are having fun with this, decrease the BHMT from less Choline and it shifts from BHMT-mediated methionine synthesis to MTR-mediated pathways, consuming 5-MTHF resulting in slower THF regeneration. Slower THF regeneration impairs the folate cycle, increasing reliance on serine as a one-carbon donor. Elevated serine flux upregulates PHGDH, which promotes IKKα-HMGB1 signaling which drives amyloid pathology and neuron death! Which brings us to probably my favorite paper from this year. "Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease" https://www.cell.com/cell/fulltext/S0092-8674(25)00397-6
I myself don't put myself in the Choline camp, but more see Alzheimer's simply as one failure mode on the metabolic estrogen axis of which is induce in certain genetic or diet configurations. In this mode it results in a number of cascading failures until death. Some genetics/diet are fairly easy to halt/undo the spiral of death which is seen in how there are some things that are known to improve Alzheimer's in some, but not all patients. I can induce Alzheimer's via the gut, diet, inflammation, adrenals, sleep, a whole host of ways, anything that starts the cascade.
An example of an unlucky genetic case is when someone has 3 CYP21A2 rather than 2, they end up with hypercortisolism and nearly always they will get Alzheimer's if there is no intervention. This is a rare genetic case, but simply a way to break the axis elsewhere with the same effect.
What is the word on the best current and ubiquitous prophylactics, like you said Vit D(3?)
For this particular situation on D3 I personally (who is not your doctor) would go with vitamin D3-loaded nanoemulsion. The reason is that Vit D influences how tryptophan is converted down the 5-HTP and serotonin path or the Kynurenine path. We want higher serotonin AND specifically in the brain. The higher serotonin means better melatonin which not only increase sleep, but increase the ERα expression which we are trying to increase... in the brain.
There is a recent study on this showing how this form can provide better results in the brain. https://www.sciencedirect.com/science/article/pii/S305047402...
In general: Omega-3, bcomplex with choline etc all have studies. Really it depends on the individual and what their genetic weakest issue is. Its old and boring, but eat healthy, don't eat before bed, exercise (dance!), and get good sleep always apply.
Are you aware of any association with stimulant treatment re alzheimers? Probably the sleep?
> with vitamin D3-loaded nanoemulsion
This is a substance that is used as a dietary supplement? Or how is it delivered?
last I heard everything amyloid/plaque burden was suspect after
https://www.nytimes.com/2023/07/19/us/stanford-president-res...
It looks very much like they are a symptom rather than a cause. They have got very good at medicines that remove amyloid/plaques, they only physical outcome was massive brain bleeds and death, plus a little
https://www.ncbi.nlm.nih.gov/search/research-news/13804/
before being withdrawn for all the reasons they resigned
https://www.pharmaceutical-technology.com/analyst-comment/bi...
absolute disaster :(
Tau and it's relationship to Amyloid, are the current top hypothesis.
Another way to look at why the removal of amyloid may not be effective in repairing damage is to think of it like a blocked pipe.
A pipe gets blocked, and the pipe itself gets damaged, causing a leak. The block can be removed, but that doesn't repair the pipe.
In my example, the pharmaceuticals are removing the blockage, but the damage is still done.
Having said that, I believe that as we learn more about what we currently call Alzheimer's, we'll discover that we've been lumping multiple diseases under a single label. I believe the amyloid hypothesis, and Type 3 diabetes hypothesis, both have merit. There may well be others.
Traumatic brain injury (TBI) can lead to the rapid formation of amyloid plaques....
So entirely possible they are simply part of how or brain deals with brain cell death.
Its possible at this point it's not a "disease" at all, at least no more than the STI we are all dieing from (our parents had sex and now we get to die).
Prior to 1900 or so, average life expectancy was something like 25 or 30, our brains simply never evolved to live as long as they do now, some people age faster than others..
The problem for the scientific basis is all the brain research has gone into plaques and ignored all the other conditions that lead to cell death and aging, it's going to be a while before other directions can be properly explored, and plaques for sure still have the momentum despite failing at every turn.
Plaques have not failed at every turn. This seems to be a myth repeated every time an article like this pops up. Yes there were specific instances of fraud, but this did not invalidate the whole research avenue. Researchers are in fact doing exactly what you suggest, and understanding plaques is a lever into those underlying dysfunctions... Like say circadian rhythm perhaps.
And I don't know why you would talk about average life expectancy when median expectancy or expectancy at adolescence are much more relevant metrics (that probably don't agree with your point).
Name a single success.
The best treatments on the market slows cognative decline measurements for up to 6 months "maybe" (could just be the result of pain relief), dates back to like 2001, and have nothing to do with amyloids.
>but this did not invalidate the whole research avenue
Indeed, multiple treatments in very expensive human trials based on the research avenue failing to show any kind of measurable clinical efficacy invalidates the research area.
The latest being from just a few days ago
https://www.biospace.com/drug-development/alector-scraps-dem...
You're confusing repairing the damage with the cause.
Just because amyloid/tau cause the damage, that doesn't mean removing them repairs.
If rust weakens a structural piece of steel, removing the rust does not repair the integrity of the steel.
There is exactly zero evidence to show they cause the damage, the only evidence that once existed to say they caused the damage used 100% faked results, which didnt emerge until after the treatments based on it causing the damage failed to show any clinical benefit and stanford launched an investigation into the prof whose students produced the evidence.
They created several treatments that stopped them forming (most prominent being biogens). The result was no difference in cognitive function vs placebo and some 20% of the people who took it suffering from a heamoralgic stroke (which they covered up).
sources please!?
there's a reason that 18% of clinical trials around drugs against Alzheimer's still target plaques
also the etiological model evolved a lot (as others pointed out, it's removing blockage after the pipe has ruptured still can lead to a sinkhole forming later)
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc...
also some nuance regarding the scientific fraud and the Amyloid mafia https://www.science.org/content/blog-post/reaction-alzheimer...
There are no sources, that is the definition of zero evidence.
Also, The fraud was found because the theory was invalidated, not the other way around. It was found that real life did not match the theory (by spending billions on human trials that all failed), so they looked back at the theory and found the results were fake.
There is however evidence that it doesnt. E.g. https://jamanetwork.com/journals/jamaneurology/fullarticle/1...
But it was and continues to be ignored.
When you say "the only evidence that once existed to say they caused the damage used 100% faked results", that is the kind of claim for which there could be evidence. What's more, it's the kind of claim that you should present evidence for when making the claim, since it's an attack on the credibility and honesty of those doing the study.
Sure, I am referring there to what started with
https://www.science.org/content/article/potential-fabricatio...
And finished with the resignation of the stanford prof engaged in it, and all the evidence that they cause cognitive imparment being retracted.
E.g.
https://www.nature.com/articles/nature04533
There is success every time we understand a new detail about how/why plaques form, how to detect them, and how to remove them. The science is pointing to a world where treating people much earlier in life (before cognitive symptoms actually appear, before tau forms) is going to prevent disease progression for the majority of people and effectively prevent Alzheimer's.
Not really true. See for instance this link
"Opponents call the amyloid hypothesis zombie science, propped up only by pharmaceutical companies hoping to sell off a few more anti-amyloid me-too drugs before it collapses. Meanwhile, mainstream scientists . . . continue to believe it without really offering any public defense. Scott was so surprised by the size of the gap between official and unofficial opinion that he asked if someone from the orthodox camp would speak out in its favor."
https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
From that link
"and only slow progression a relatively small amount."
They don't even do that. they _do_ remove plaques, they _do not_ have any statistically significant effect on MMSE degradation.
plus I only see the comments that point out the entire scientific basis for them was based on faked research.
The way I had it "simply" described was "the plaques are basically dead brain cells, the problem is the brain cells rapidly dieing, not cleaning up the corpses afterwards".
either way, the faked research set dementia research back at least 2 decades and wasted billions of dollars on failed medications with no benefits and horrific side effects (that they tried to cover up).
Dale Bredsen says the fundamental nature of Alzheimer's is a network insufficiency.
At minutes 0:16-0:51 in https://x.com/MetabolicFactor/status/1918558438440739258
Yep; this has frustrated me for two decades.
Is there anything known we know reduces risk?
I'm far from an expert but maybe the air we breathe is toxic? It makes stuff oxidize and go bad. It just takes enough of this poison and that's it.
> maybe the air we breathe is toxic?
I suppose since atmospheric oxygen is mostly of biological origin, yes, you're technically correct in labelling oxygen in the air as a toxin.