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.
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.
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.
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
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).
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.
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).
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)
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.
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.
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.
"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."
"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).
That doesn't mean it was used for speech and language: evolution frequently finds a new purpose for a gene, and the previous purpose does not have to be human-comprehensible.
Tying this to APOE, specifically e4 which has an increased requirement for choline and when choline levels are low there can be a metabolic push that leads to elevated PHGDH activity and consequently, increased serine synthesis. That is a neat connection and maybe why when we study choline supplements we see positive results.
That is super interesting, as is the relationship between choline and sleep. With restorative sleep function, and specifically slow-wave activity, considered to be a significant driver of AD.
> In conclusion, our findings suggest that moderate dietary choline intake, ranging from 332.89 mg/d to 353.93 mg/d, is associated with lower odds of dementia and better cognitive performance.
Gemini tells me that amounts to ~850mg of alpha GPC or ~1900mg of citicoline. Eggs it is then.
Claude tells me that’s 4-5 eggs per day or 5x150 mg alpha gpc capsules.
The eggs would be a lot more expensive in both time and materials plus most egg farms seem cruel (especially male chick killing)… I’m leaning towards alpha gpc supplements.
This stuff goes over my head, but perhaps one can take something to lower TMAO (I see EVOO, allicin, resveratrol, PQQ from a cursory search) to offset choline supplementation. This is assuming TMAO is the cause of increased disease risk and not just a biomarker.
I have a several complex genetic problems that I give to LLMs to see how well they do. They have to reason though it to solve it. Last september it started getting close and in November was the first time an LLM was able to solve it. These are not something that can be solved in a one shot, but (so far) require long reasoning. Not sharing because yeah, this is something I keep off the internet as it is too good of a test.
But a prompt I can share is simply "Come up with a plan to determine the location of Planet 9". I have received some excellent answers from that.
Answer quality is a fair test of regurgitation and whether it's trained on serious articles or the Daily Mail clickbait rewrite. But it's not a good test of reasoning.
The recursive one that I have actually been really liking recently, and I think is a real enough challenge is: "Answer the question 'What do you get when you cross a joke with a rhetorical question?'".
I append my own version of a chain-of-thought prompt, and I've gotten some responses that are quite satisfying and frankly enjoyable to read.
Yeah. In the example I shared, my charitable interpretation would be that it's identifying the trick question as "a setup" where the punch line is the confusion the audience experiences. And in a meta sense, that would also describe the form of the entire chat.
This depends heavily on how you use these and how you have things configured. If you're using API vs web ui's, and the plan. Anything team or enterprise is disabled by default. Personal can be disabled.
They probably don't, but it's still a good protection if you treat it as a more limited one. If you assume:
[ ] Don't use
Doesn't mean "don't use," but "don't get caught," it still limits a lot of types of uses and sharing (any with externalities sufficient they might get caught). For example, if personal data was being sold by a data broker and being used by hedge funds to trade, there would be a pretty solid legal case.
> it still limits a lot of types of uses and sharing (any with externalities sufficient they might get caught)
I don't understand what you mean
> For example, if personal data was being sold by a data broker and being used by hedge funds to trade
It's pretty easy to buy data from data brokers. I routinely get spam on many channels. I assume that my personal data is being commercialized often. Don't you think that already happens frequently?
I honestly would not put on a textbox on the internet anything I don't assume is becoming public information.
A few months ago some guy found discarded storage devices full of medical data for sale in Belgium. No data that is recorded on media you do not control is safe.
Oh, so now EVERYTHING is fake unless personally verified by you in a bunker with a Faraday cage and a microscope?
You're free to distrust everything. However, the idea that “I don’t trust it so it must be invalid” isn’t an solid argument. It’s just your personal incredulity. You asked if there’s any verification and SOC-2 is one. You might not like it, but it's right there.
Insight Assurance is a firm doing these standardized audits. These audits carry actual legal and contractual risk.
So, yes, be cautious. But being cautious is different than 'everything is false, they're all lying'. In this scenario, NOTHING can be true unless *you* personally have done it.
I merely said I don't trust the big corporation with a data based business to not profit from the data I provide it with in any way they can, even if they hire some other corporation - whose business is to be paid to provide such assurances on behalf of those who pay them - to say that they pinky promise to follow some set of rules.
Not a false dichotomy. I'm just calling out the rhetorical gymnastics.
You said you "don’t trust the big corporation" even if they go through independent audits and legal contracts. That’s skepticism. Now, you wave it off as if the audit itself is meaningless because a company did it. What would be valid then? A random Twitter thread? A hacker zine?
You can be skeptical but you can't reject every form of verification. SOC 2 isn’t a pinky promise. It’s a compliance framework. This is especially required and needed when your clients are enterprise, legal, and government entities who will absolutely sue your ass off if something comes to light.
So sure, keep your guard up. Just don’t pretend it’s irrational for other people to see a difference between "totally unchecked" and "audited under liability".
If your position is "no trust unless I control the hardware," that’s fine. Go selfhost, roll your own LLM, and use that in your air-gapped world.
If anyone performing "rhetorical gymnastics" here is you. I've explained my position in very straightforward words.
I have worked with big audit. I have an informed opinion on what I find trustworthy in that domain.
This ain't it. There's no need to pretend I have said anything other than "personal data is not safe in the hand of corporations that profit from personal data".
I don't feel compelled to respond any further to fallacies and attacks.
You’re not the only one that’s worked with audits.
I get I won’t get a reply, and that’s fine. But let’s be clear,
> I've explained my position in very straightforward words.
You never explained what would be enough proof which is how this all started. Your original post had,
> Do you just completely trust them to comply with self imposed rules when there is no way to verify, let alone enforce compliance?
And no. Someone mentioned they go through SOC 2 audits. You then shifted the questioning to the organization doing the audit itself.
You now said
> I have an informed opinion on what I find trustworthy in that domain.
Which again, you failed to expand on.
So you see, you just keep shifting the blame without explaining anything. Your argument boils down to, ‘you’re wrong because I’m right’. I also don’t have any idea who you are to say, this person has the credentials, I should shut up.
So, all I see is the goal post being moved, no information given, and, again, your argument is ‘you’re wrong because I’m right’.
Think questions where there is a ton of existing medical research, but no clear answer yet. There are a dozen alzheimer's questions you could for example ask which would require it to pull in a half dozen contradictory sources into a plausible hypothesis. If you have studied alzheimer's extensively it is trivial to evaluate the responses. One question around alzheimer's is one of my goto questions. I am testing its ability to reason.
There's so much text on this already, it's unlikely to be even engaging any reasoning. Or specifically, if you got a few existing answers from philosophy mashed together, you wouldn't be able to tell it apart from reasoning anyway.
The author also asks "If you were stranded on an island (or small hostile planetoid), what books would you want to have with you?" which I also can't answer.
I would fall into the category of someone who does research as leisure. I have been slowly unraveling the genetics behind gender dysphoria. Yes I have borrowed a few biology books from libraries, but it has mostly been reading 70 years of research papers, piecing together all the evidence to make a hypothesis, comparing it to all the research data and iterating. In the last year I have also started getting a fair number of WGS (Whole Genome Sequenced) files, and I have a whole separate pile of anecdotal that just because it isn't published doesn't mean I can ignore it either. These are about as far from books as you can get. It is something I do for leisure, so my investigation has been somewhat random, following whatever I found interating at that time including dead ends. Been doing this very open ended research for years now and at this point we have a really solid understanding of it, so the edge cases are actually now the fun stuff. I never would have made anywhere near the progress I did if I had been forced to start with reading a bunch of random unrelated biology books.
3 of the 4 dna samples show signs of nonclassic CAH. This limited their reproduction abilities as 50% of babies would have CAH and die at birth until they integrated with proto-humans and had higher genetic diversity.
I have had one of these for years and the right size makes all the difference. Some fun things include the ability to feel where the metal studs are in building walls, where the electrical lines are under the ground and of course the microwave. The most interesting part is how I conceptually had thought of electrical fields as 2d (because of pictures and school), but in reality they are 3d and so it is like reaching into a sphere of various sizes, the deeper you go in this sphere the stronger the field.
May I ask if you have a recommended style or material that you prefer for sensing? The idea of sensing EM fields is fascinating to me but I've never quite made the leap to an implant. I didn't realize these kinds of rings exist.
If you mean ring type I don't remember which one worked best, sorry.
As for my favorite EM field there is a nearby street with buried powers lines and transformer boxes at ground level. As you walk the street to the main street each box has a bigger EM sphere and I like to let my hand coast over each sphere. It isn't a sphere per say, but only in the sense that at at certain depth in the field the density (for lack of a better term) becomes high enough that I can feel it and it is like a boundary line
Because there was general layoffs of the workers in the previous year or two? There is a fairly formulaic way that companies tighten belts. First you do layoffs, get rid of projects that will never make money, reduce headcount for orgs that grew fat, etc. At the same time you explore offshoring (especially as it keeps the same number of headcount under a vp for less cost). Then there is a round of cleaning up the management layer, making sure everyone has a minimum number of reports, moving some managers back to being leads/IC etc.
This was all formulaic and the more experienced directors and VP's back in 2022 knew this and immediately started playing the new corporate game to win in the long run.
Naltrexone in high doses takes away all pleasure by blocking opioid receptors (low doses do too, but it is different when only a few hours). So there is no reward for drinking or eating if that is why you are eating. If this is not why you eat it will be less effective.
Bupropion acts as a norepinephrine–dopamine reuptake inhibitor. Importantly it doesn't directly raise your serotonin. If you are a night owl, have trouble falling asleep etc you might have low serotonin to start and this could be bad for you.
Both of these are associated with suicidal thoughts. There is a reason HIMS requires your health info before suggesting drugs. I would flag the parent as providing dangerous information.
> Conclusions and relevance: In this cohort study, a history of upper gastrointestinal MD was associated with elevated risk of developing a clinical PD diagnosis. Increased vigilance among patients with MD for future PD risk may be warranted.
Associated is the key word. The washington post sensationalizes it to "may begin in the gut"
association indicates possibility of causation. The washington post used the right wording here.
While association does not imply causation, you very much need an association in order to establish causation. You actually need establish two associations in order to verify causation, so the existence of one type of association is already an indicator for "may begin in the gut".
But practically you need to associate cause and effect and lack of cause and lack of effect. That is two associations, and in one association the experimenter himself must deliberately influence the experiment.
This verifies cause from a practical perspective. From a technical perspective causation was not verified. Because technically you need to verify both effect and lack of effect from one population on the same event and the only way to do that is time travel.
We influenced the experiment by creating the causation but by doing that we can no longer know what would’ve happened if we didn’t create the causative precursor and thus we can never truly know if the event actually caused the effect.
Technically sometimes causation can be verified. Say you break your arm in a car crash - it's pretty clear what caused what. I'll give you that with things like gut problems and Parkinson's it's tricker.
It really isn't. Maybe your arm was osteoporotic or weak from a prior incident, and it broke due to a trivial pressure injury when the ambulance workers were loading you into the ambulance.
The point is that it's pretty clear only when it can be mathematically proven, and at all other times it's based on some idea of probability. In the case of this article, a causal association seems quite probable to me.
I’m of course referring to formal verification. Which means give me 100 percent concrete proof the car crash was causative. This is science and this is what all of science strives and ultimately fails to achieve.
For your example you didn’t prove anything. You gave me an arbitrary example and hoped I would understand your point through an example. I do understand your point but you failed to understand my point.
Your example is only an empathic offering of understanding but it doesn’t offer proof of your statement. Show me a formal proof of something that was causative. Anything.
You will find that on multiple levels of resolution not only can causation not be formally proven but that science can never prove anything in reality. Proof is the domain of maths and logical games of axioms and theorems we play with arbitrary rules, it does not actually apply to reality.
The paper is about the gut-first hypothesis of Parkinson disease (PD), I don’t think the Washington Post sensationalized it that much. And the p-values they find are pretty amazing. P<.001 and still P=.01 after covariate adjustment.
I agree. They know dopamine makes things worse for PD pateints.
My Theory: The reason that Dopamine fails is because they do not have low dopamine, but low energy for the dopamine receptor. The dopamine receptors are G Coupled Protein receptors that need GTP to function. So if you are low in the purine GTP then it does not matter how much dopamine you make.
Giving these patients dopamine works, but then fails, because it depletes the cells of GTP.
Sure. Interesting hypothesis. More research needed.
*edit, for the record, for me, as a postdoc, a hypothesis, while more structured than mere speculation, is still an unproven explanation that requires rigorous testing and peer review before it can be considered established scientific knowledge, and thus remains speculative.
The p-values don't say anything about the size of the effect. With a large sample size, they are almost guaranteed to be small. In fact, the confidence interval after covariate adjustment comes very closing to containing the value 1, which suggests no substantive change between the groups.
I was curious so I searched. I wonder if other conditions set up parkinsons? (Also disorders might != damage)
Causes and Diagnoses of Mucosal Disorders
The causes of mucosal disorders are generally bacteria, viruses or fungi, such as yeast. A weakened immune system, stress or dietary deficiencies can make you more prone to a mucosal disorder.
Mucosal disorders can develop in a variety of ways:
- Candidiasis is often caused by humid conditions, damaged skin or a depressed immune system.
- Canker sores are the result of a condition called aphthous stomatitis, and brought on by a weakened immune system, food allergies, viruses, bacteria and poor nutrition.
- Herpes is spread through skin-to-skin contact such as kissing and sexual intercourse. It can also be passed via a glass or lip balm of someone who has the herpes simplex virus. It can be contagious even when no lesions are present.
> 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.