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> …small amounts of clumping tau protein in the brain and cerebrospinal fluid, which lead to Alzheimer's disease.

I don’t think this should be stated as a proven fact anymore, given the doubt now cast over the amyloid hypothesis

This is a nice summary of the case: https://podcasts.apple.com/us/podcast/plain-english-with-der...

The problem with the amyloid hypothesis is most likely not that it is wrong, but that it is incomplete, and I would say that is the problem with this test as well.

I work in neurotech/sleeptech, and AD researchers are using (or want to use) slow-wave enhancement to prevent and possibly manage AD.

However, the test for AD is still a psychological tests along with neuroimaging to look for tau tangles and amyloid plaque build up.

It has been discussed that we may be looking at multiple different diseases which have similar symptoms and without completely understanding the disease itself, we are categorizing them as AD, though they may have different pathways.

Though we can't ignore the challenges to the amyloid hypothesis, we also shouldn't completely throw it out. Most of the experts I've spoken with still believe it is the best hypothesis we have, but that we also should not ignore other possibilities.

It surprises me that some obvious clues to treatment are passed over as I guess they don't fit the politics? Like

>A team of researchers in Jerusalem, he says, decided to look at patients who survived bladder cancer and compare dementia prevalence among patients treated with BCG and those who weren’t. “Do they differ in the rate at which they get Alzheimer’s disease?” The answer is yes – the BCG group appeared to get 75% protection against Alzheimer’s. A number of studies have now found varying levels of protection from BCG, with an average, according to one meta‑analysis, of 45%.

There's a lot of evidence a lot of it is set off by infectious microbes which can be treated in the usual way. (From https://www.theguardian.com/lifeandstyle/2024/dec/01/the-bra...)

The 'politics' puzzles me. Maybe the head of department got fame for hypothesis A and feels his power or money is threatened by hypothesis B? It's not what science should be about.

(There was an entertaining angry Sabine Hossenfelder youtube a few minutes ago on the corruption of science just wasting money, but really letting people die of Alzheimer's is worse. https://youtu.be/shFUDPqVmTg)

I think the quote you provided shows exactly why it is so difficult.

When you are comparing a group who survived bladder cancer and then looking at those numbers and figuring out if the bladder cancer treatment had a preventative effect on Alzheimer's, many many things are being conflated together.

You initially have survivorship bias of those who were alive after bladder cancer. How many of the bladder cancer people had AD, or another disease? Though I'm sure the BCG treatment helped in their treatment of bladder cancer, did these people respond better to the bladder cancer treatment because of other factors? Did they have better lifestyle than those who did not, less inflammation, better diet, etc etc.

How many women were in the study? AD affects twice as many women as men. If AD is an infectious disease, why would this be? Type 3 Diabetes is a strong candidate as an alternative theory to AD, but Type 2 Diabetes, though more damaging to women, does not occur at twice the rate as in men? So why would this be?

Again, I'm not saying other theories are wrong, but everything is VERY difficult to prove.

The Amyloid hypothesis, which I would also label as the sleep theory of AD, is tied to reduced glymphatic function, reducing the brain's ability to clear metabolic waste. Why would this affect women much more prominently than men? Motherhood and Menopause, both of which are very disruptive to women's sleep.

Of course maternal diabetes can also play a significant role.

I completely agree with Sabine Hossenfelder and you that improvements need to be made to the scientific process, including publishing of negative findings, and improved open discussion regarding published papers. I suggested to someone recently that they create a HackerNews of research papers and we don't just have citations, but open discussion of people expert in the space.

There are letters in publications, but that is not directly tied and linked back to the paper. A friend was developing something similar to this years ago, but was never able to find enough traction or a business model that makes it work.

I understand that women get AD more than men simply because they live longer. Is this not true?
> Why would this affect women much more prominently than men? Motherhood and Menopause, both of which are very disruptive to women's sleep.

On the other side sleep apnea is 2-3x more prevalent in men.

There‘s also a weird relation with the oral microbiome. Probably not that surprising, seeing how much translocation is actually happening between our microbiomes.

Just an n=1 ofc, but someone in my family got all their remaining teeth pulled and replaced with implants, and afterwards, within 3 years went from asymptomatic to dead from AD. The progression was mind boggling. I‘ve wondered for a long time whether the oral work was related to this - the surgery caused so much damage that it certainly exceeded capacity to heal, opening the doors wide for any pathogens.

"The problem with the amyloid hypothesis is most likely not that it is wrong, but that it is incomplete,"

If the hypothesis is that amalyoid causes AD, then I think we've disproved that (even with your statement that it's incomplete). If I remember correctly, there are individuals who have amalyoid without developing AD, or who have had their amalyoid levels reduced without improvement. At this point, it seems that amalyoid is more of a symptom than a cause. But you are correct that the data is dirty - many studies have not tested for amalyoid itself, instead relying on clinical diagnosis, and subsequent studies are finding at 25% of mild to moderate AD may be other forms of neural degeneration. So many of the AD studies out there focusing on amalyoid reduction are garbage because many of them happened before being able to use imaging to test amalyoid levels.

This is what I mean by "we are likely looking at different diseases". Something that would be diagnosed as AD, but without amyloid levels (if it is decided that this the correct marker to look at).

It's as if we were to look at diabetes, and then not recognize there are (at least) two types of diabetes, with VERY different causes, and recommended treatments.

Damn! I know nothing about AD and while reading these comments you mentioned sleep tech. I didn’t understand the connection or what amyloid hypothesis even was, so looked it up.

As someone who’s on < 4 hours of sleep a day with at least one day for 36 hours straight awake a week, umm… should I be worried?

Yes, you should be very worried. Imagine accumulating trash in your house—you take some out, but you never throw away all of it. Each time, some remains. Now, imagine what happens after a few decades. In this example, the house represents your brain.
Agree strongly with you. This statement make Alzheimer’s into a wonderfully “simple” monogenic disease like Huntington’s but all age-related disease have many complex interwoven weaker and stronger causes—-even Huntington’s disease in which the same mutation type (numbers of CAG mutations in neurons) can cause symptoms over a 20 year range.

Too bad that headlines are inherently short and sometimes misleading. Simple sells.

Is it not still the case that they do correlate, and therefore the article talking about them as biomarkers is not making the mistake you think it is (as if it was talking about them as the thing to get rid of to prevent Alzheimer's)? Because "lead to" is not the same as "causes".

Or has latest research shown that even a non-causal link should be dismissed?

Ok “lead to” might not be exactly equivalent to “causes”, but it’s not even accurate because tau doesn’t ALWAYS lead to Alzheimer’s. The correlation is not strong. People have tau and no Alzheimer’s and other people have Alzheimer’s symptoms and no tau. So what good does it do you to test for tau? It’s a higher probability of Alzheimer’s, but not nearly definitive. I suspect that if this test is productized, this nuance will be lost on many doctors.

Seems like a good test to give someone so you can scare them into taking a drug that also has very little evidence of effectiveness.

"Lead to" is a synonym for "causes".
It can be used that way, but not always. In fact, traditionally your way is the less common usage.

A path of breadcrumbs leads to the gingerbread house, despite the house not existing because of the path (or a road leading to a house, to get away from witches).

Unless you mean that in medical research it's universally agreed to only use it in that way? I'm sceptical that's the case but could be convinced...

(Either way, "lead to" obviously isn't at all clear enough if they did intend to mean "points towards, without causation".)

I've seen this point brought up many times over the years and yet research in this direction seems to continue, so I think there must be more to it. I asked chatgpt about it, and it claims that the controversial paper was influential but it was more about a certain sub-hypothesis that got called into question after that rather than the entire thing.

Now I know that bringing up chatgpt is frowned upon here but I thought I should make an exception for this case as its not so easy for me to answer otherwise.

You might enjoy “How Not To Study A Disease: The Story of Alzheimer’s” by Karl Herrup (2023, MIT Press). Great sad overview of the hegemony of the Abeta hypothesis that now has a Tau hypothesis buddy.

https://mitpress.mit.edu/9780262546010/how-not-to-study-a-di...

> Catching these clumps early while still in minute quantities can enable effective intervention

I wonder what interventions they mean here. Drugs, lifestyle changes?

Probably not going to be super popular but maybe heating your brain for 20 years? https://text.npr.org/nx-s1-5293253
Elevated heat shock proteins actually makes good sense as a reason. We should check ClinicalTrials.gov using the key words: Alzheimer and “heat shock protein”.

I just tried anf found a total of 130 trials using Heat shock proteins 70 or 90 (HSP70 and HSP90) and with very few exceptions they are all cancer trials.

Monoculture.

Sauna sounds good at this point.

Would working out hard (HIIT), that makes the heart rate go up a lot (~180bpm) generate enough heat in the body for a similar effect?

Basically, can I replace sauna with 30 minutes of vigorous cardio?

Edit: I see this was asked already - https://news.ycombinator.com/item?id=43062169

So sauna/Turkish bath/hot-springs users have reduced incidence of Alzheimer's?

If going to the sauna daily is all it takes to prevent it, that would be quite a thing!
Is Alzheimer's less prevalent in sauna going populatioo?
Presumably, a newer generation of anti-amyloid or anti tau agents. There are current gen ones (targeted monoclonal ab ) which aren’t that incredibly effective but there’s some thought that maybe that’s due to treating the wrong patients at the wrong time, vs starting therapy earlier on
Didn't it turn out that the amyloid plaque hypothesis was based on a fraudulent paper?
Not exactly. There are "issues" with one of the early papers, and I believe some other follow-up papers, but not all research had these issues.
We've been developing Sleep slow-wave enhancement tech for the last few years, and studies are showing promise as a potential prevention and management of AD.

These links were not using our tech, but are based on the same principles of phase-targeted slow-wave enhancement. We have an enhanced protocol aiming to overcome some of the issues these researchers experienced with previous implementations.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10758173/ https://jcsm.aasm.org/doi/10.5664/jcsm.10778

Nothing. We don't know of an intervention for Alzheimer's. Early detection can enable effective intervention, but in this case it doesn't.
We have a lot of correlations and theories and now we can test over more than 10 years and see what happens when with patients where we have successfully kept these markers down from a much earlier start. I just hope they control correctly for brain bleeds and premature death.
That will be a fun set of experiments.

As far as I'm aware, we currently have no evidence to suggest whether the appropriate model for this protein accumulation is more "it's like a cancer growing on your organ" or "it's like a scab growing over an open wound".

Are scabs markers of injury? Of course.

Could we reduce injuries by preventing the development of scabs? No, that's a new horrifying medical condition called hemophilia. In the general case, it's rapidly fatal.

This is something that really bothers me about the current craze for suppressing inflammation. In that case, we already know that inflammation is like scabs, a defensive reaction against some other problem. For Alzheimer's, we don't know anything.

There’s been evidence recently that GLP-1 Agonists can delay the onset of Alzheimer's symptoms. Look up the evoke and evoke+ trials. This might be the first “real” treatment for Alzheimer’s, and it’s relatively low risk.
GLP-1 agonists are life extension drugs, they cure way more than just weight.
At my company, we have been looking at understanding how the beta-amyloid interacts with toxic metals in the brain that lead to formation of plaques. We have been studying the use of quantum computers for such complex reactions. Most of us come from quantum computing and quantum chemistry background, so, relatively low experience with biological aspects. And as we dug deep into the reactions and made some good progress, a few established biologists got interested and asked questions around the beta-amyloid hypothesis itself. So, I dug a little deep into the whole field, most of my information comes from the following article: https://www.science.org/content/blog-post/faked-beta-amyloid... After doing some independent reading, following were my big take aways: - figuring out the truth in this area is incredibly hard. Science already suffers from social quirks like, scientists find it easy to say, 'hey, we replicated the decades-old established results and built something on top of it' rather than risk shaking the fundamentals of the field. All the big shots who did research on Alzheimer's got a lot of money from NIH for decades. Most of the projects were around beta-amyloid and these grants do not stop. So, if suddenly the field agrees that the hypothesis is incorrect, then a lot of people would lose jobs and livelihoods overnight. So, it is not just a scientific problem, the social-economic elements are quite powerful in this field. - Another fascinating thing I learned was that at this point Alzheimer's and beta-amyloid are quite intertwined. In fact, if a patient has Alzheimer's like symptoms but does not have a high concentration of beta-amyloid plaques then, the doctors may bucket such symptoms another form of dementia, with high probability. Coming from a Physics background, I found it incredibly fascinating that we depend on some loose markers and symptoms to define such complex diseases. And as you may have noticed from some of your personal experiences, symptoms sometimes can overlap in diseases and many times not everyone experiences the same symptoms and in fact a single human may experience different symptoms from getting the same disease. - So bottom line, not only we do not fully understand the pathophysiology of Alzheimer's, but there's a chance that we do not even understand what even is Alzheimer's.
There's grants and studies going on for all kinds of treatments for Alzheimer's. Amyloid may be the biggest category, perhaps undeservedly, but it's still a minority of them. Also I think your article may be a bit out of date. Haven't there been more successful studies recently?

I certainly agree about how weak the "ground truth" really is when it comes to these diseases. The theories are necessarily always going to be highly simplistic models that are ultimately wrong but sometimes useful. The only real causation they can show is from studies which show a drug works. And even then they usually don't really understand why (though it's human nature to think that if you can predict something successfully your theory is proved to be true).

There was this super interesting new research..

https://www.sciencealert.com/alzheimers-may-not-actually-be-...

Alzheimer's may not be primarily a brain disease but rather an autoimmune disorder where the brain's immune system mistakenly attacks its own cells, with beta-amyloid playing a central role.

There is a growing consensus that focusing solely on beta-amyloid has led to stagnation in treatment development, prompting researchers to explore alternative theories and treatment pathways.

Also there is potential fabrication of data in a key 2006 study linking beta-amyloid to Alzheimer's and the FDA's approval of aducanumab, which has faced criticism for its incomplete data.

Until we have a way to actually treat Alzheimer's, this seems like a mixed blessing at best. I suppose you could get your affairs in order, you but won't be enjoying much of those 10 years.
There are multiple pharmaceuticals which are used to slow the progression of the disease.

We're in the neurotech/sleeptech space and have been developing slow-wave enhancement tech for the last few years, our technology is beginning to be used in clinical studies.

These studies (using other less effective devices) have shown promise https://pmc.ncbi.nlm.nih.gov/articles/PMC10758173/ https://jcsm.aasm.org/doi/10.5664/jcsm.10778

> There are multiple pharmaceuticals which are used to slow the progression of the disease

My father tried a number of them. Some quite lovely side effects on those—-it was basically the worst night terrors ever or the shits. Neither of which makes the already difficult job for Alzheimer’s patient caregivers any easier, nor does it improve the quality or dignity of the patient’s life either.

My father’s torture with Alzheimer’s ended last year. Slowing the disease may not always be the best approach in my opinion in hindsight. If anyone is currently going through this with a loved one, my advice is to think hard about the value of slowing the disease if the patient has reached the moderate dementia stages.

I am sorry you had to go through that. My uncle had Alzheimer's, and though I didn't hear about those stories, you are correct, the disease itself is incredibly cruel.

When I think of "slowing the disease", I'm not thinking of the later stages, which I agree with you, what's the point.

We should be (and my company is) more focused on increasing quality of life, not time in illness.

Why does one need a looming Alzheimer's issue to get one's affairs in order?

Wills, etc should be done decades before that stage of life. As soon as one has any spouse or dependents one should do all that jazz.

There would be a different level of detail if you knew for a fact you were going that direction. Living wills and power of attorney are often fairly generic, as you don't know what situation will arise that will make them necessary. Well, now you would know a specific likely scenario, and you can get specific about each step of the expected progression.

You may even change your financial plans - you would know that you need to get all the life you can out of the next 10 years, and you know you will have above average costs for medical care after those 10 years. I do not envy the work/life balance decisions to be made in such a scenario, but at least you get the opportunity/burden to make them.

It was always strange to me that scientists (people that are expected to be rigorous in their experimentation and analysis) would not include history in their analysis.

However, the Latin root of the word "science" is about cutting or taking something apart and zooming in. Perhaps another word is needed to describe the process of putting whatever is scientifically discovered within a larger context to account for so many variables that are ignored during the scientific process.

I personally suspect that all the biomarker stuff are really just the biochemical remnants of processes that begin at the sociocultural level.

>I personally suspect that all the biomarker stuff are really just the biochemical remnants of processes that begin at the sociocultural level.

That is a bit extreme. The sun is still set to die out in five billion years, regardless how much we talk about it. Its entirely possible that Alzheimer's has an origin which goes beyond any specific social circumstance, though I doubt it.

"Math"?

As argued in https://news.ycombinator.com/item?id=43053625

Etymology: "learning"

This is about a new cerebrospinal fluid assay. These days there are also blood tests, which are obviously way easier to take and much less unpleasant:

https://www.nature.com/articles/s41591-024-02869-z

https://www.fujirebio.com/en/products-solutions/lumipulse-g-...

well, now we have excellent news <3