[glaugh]

> …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...

[pedalpete]

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.

[tim333]

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)

[pedalpete]

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.

[circlefavshape]

I understand that women get AD more than men simply because they live longer. Is this not true?

[pedalpete]

I think that was an early and somewhat naive understanding of why. I wouldn't say it is not true, but the 5 year lifespan difference resulting in 50% more cases of Alzheimer's in women seems an oversimplification.

[Qem]

> 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.

[manmal]

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.

[pedalpete]

I agree to a point, but you also have to consider, why did they have to get their "remaining teeth pulled"? It is entirely likely the AD was present before the teeth were removed.

I had an uncle with AD, and he hid it VERY well for quite a few years. We would have thought he was asymptomatic, but we suspect it was just that we didn't know.

[manmal]

Yes that may well be.

[tim333]

I guess it only takes one bad pathogen to get in and it's hard to know what happened without scientific testing.

The Guardian article I linked in another comment has for one guy "sample of his cerebrospinal fluid was taken and revealed a fungal infection..." which it shows it's possible at least to some extent to test for this kind of stuff. (article https://www.theguardian.com/lifeandstyle/2024/dec/01/the-bra...)

It seems a bit of an under explored area. I suspected something like that with my dad who had a long deterioration of nerves/mind but current medics don't seem to regard it as a thing to do. It's more get your affairs together before the care home/death. While the guy in the Guardian article guesses that likely more than 50% of dementias are treatable infections.

[m463]

I've heard prion disease can be transmitted by dentistry. Makes me wonder.

[Madmallard]

How old were they when this happened?

[manmal]

About 60

[giantg2]

"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.

[pedalpete]

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.

[alfiedotwtf]

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?

[lossolo]

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.

[alfiedotwtf]

OK thanks for that, I’ll have to do more reading

[robwwilliams]

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.

[swores]

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?

[dimal]

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.

[kadoban]

"Lead to" is a synonym for "causes".

[swores]

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".)

[kadoban]

"Lead to" physically, in terms of locations, means that, but I have never heard it mean "preceeds" and not "causes" in terms of events.

Yeah, I think they worded it incorrectly.

[im3w1l]

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.

[robwwilliams]

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...