[mobilejdral]

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.

[amenhotep]

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.

[mobilejdral]

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.

[Obscurity4340]

What is the word on the best current and ubiquitous prophylactics, like you said Vit D(3?)

[mobilejdral]

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.

[DarkmSparks]

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 :(

[ransom1538]

Is there anything known we know reduces risk?

[yard2010]

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.

[JumpCrisscross]

> 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.