Protein biomarkers predict dementia 15 years before diagnosis in new study | Hacker News Reader

Protein biomarkers predict dementia 15 years before diagnosis in new study

warwick.ac.uk

225 pointsao9847 comments

One caveat is that this is necessarily a retrospective study. The authors looked at historical data from the UK Biobank, ran a regression, and found these genes. So, it’s not really clear if these genes are actually causing dementia, or if they’re just related to a common cause, or (most likely) tied together through some very complicated web of biological mechanisms.

That said, they’re interesting genes. GFAP is expressed in astrocytes, which are glial cells. These perform a lot of tasks in the brain, but they seem important in protecting neurons from toxic stresses. So, this may give us some additional insight into the role of glial cells like astrocytes in dementia.

If it's predictive, does it matter?

Yes it does. Think of typical notions of statistical significance when testing one new idea prospectively, say the concept of a p-value, or the AUC used in the paper. Now think instead of a rich dataset and you are free to fish for any of the possibly tens of thousands of signals for one signal or a combination of signals that match your result. Loosely speaking you are overfitting and the threshold for being surprised or having statistical significance is now much more strict.

https://en.wikipedia.org/wiki/Bonferroni_correction

Sure, but let's say that we test this and it is predictive on new data (not overfitting), but we have no idea at all how it works. It's still a useful test.

The retrospective regression on a specific dataset might discover a true correlated quantity, if any true correlated quantities were there and their signal was more prominent than the combinations you get from the noise. However, this analysis will always discover a quantity that correlates, by design. These retrospective studies can prompt prospective studies for a correlated quantity (a biomarker in this case) and the careful analysis of the retrospective study methodologies and results can suggest the design of such prospective studies; if a prospective study works, then that is fantastic. The retrospective studies are mostly there for statisticians to figure things out for future tests, except when the signal is simple and phenomenal.

I guess one issue is that our environment changes so that what was predictive for the past isn't for the present day.

Can gene expression be affected by pollutants more common decades ago like abestos, coal-dust or leaded petrol? It would be frustrating to only discover this in 15 years time.

But it is not a retrospective study? They took blood samples at baseline from all participants, and later on some developed dementia?

For this to be prospective rather than retrospective, they would have developed the risk model beforehand.

GFAP as dementia biomarker isn't a new discovery. Here's a 2023 meta-analysis that used papers as old as 2020.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177296/

> Proteins (for example Glial Fibrillary acidic protein, GFAP) had previously been identified as potential biomarkers for dementia in smaller studies, but this new research was much larger and conducted over several years.

The article (University press release) does mention this... but seeing a known suspect in the biomarker list would lend some confidence to any novel biomarkers found. So, it's good to see multiple studies having similar hits.

Totally a good thing. There's a very long list of biomarker failures, and there's lots of analysis into why so many biomarkers fail in clinical applications.

One starting point for reading: https://academic.oup.com/clinchem/article/59/1/202/5622131

They mention this in the article, and of course, the scientific method means we _want_ to have more than one suggestive meta-analysis before we declare any kind of "discovery" at all.

https://www.nature.com/articles/s43587-023-00565-0

^ direct link to the paper.

"... plasma proteins, GFAP, NEFL, GDF15 and LTBP2 consistently associated most with incident all-cause dementia (ACD), Alzheimer’s disease (AD) and vascular dementia (VaD), and ranked high in protein importance ordering."

> Of 1,463 proteins analysed, aided by with a type of artificial intelligence known as machine learning, 11 proteins were identified and combined as a protein panel, which the researchers have shown to be highly accurate at predicting future dementia.

I understand that press releases are intended for non-technical folks but I don't get the point of this description. Is it assumed that machine learning is less understood than artificial intelligence?

a scientists view of the common man's knowledge is very distorted

It's always encouraging to see progress in disease prevention. As a young person, I'm looking forward to what the medical field will be like when I'm 70.

its not disease prevention its correlation.

Finding a novel correlate that precedes the other observed effects of the disease in question is progress in prevention.

people thought for years that amyloid plaques were driving the disease only to be proven utterly wrong

you might want to have a bit of humility when dealing with complex systems

Hmm. Are you saying that the fact that some knowledge is wrong means that it doesn’t represent progress?

Correlation isn’t “cure” — we don’t even know if it’s predictive — but that doesn’t mean it’s not progress.

progress is measured by:

- identifying mechanism of action

- identifying therapeutic levers

- testing drugs and ahow that they can do something

we are not even at the first step with these biomarkers. observational studies are super noisy

How can you identify a mechanism of action if you don't have any idea of what the possible agents are? Don't you first have to identify some of the molecules that may be involved, before you figure out which ones are causal and how that causality plays out?

That seems to be the point of this paper.

I agree with you. I think being proven utterly wrong is a huge accomplishment nonetheless. We shouldn’t be sure of ourselves, but we should treasure any progress even if it’s in the form of negating causes rather than isolating them.

‘Utterly wrong’ is a harsh conclusion. You may want a touch of humility yourself. Amyloid plaques are the defining feature of AD and assuredly provide vital clues about the biomolecular processes driving AD across the brain. There is renewed interest in the what causative role amyloid plays [1]. Whether plaques are causative or a byproduct is an open question, especially when we consider the heterogeneity in neurodegenerative diseases. AD itself probably is an umbrella term capturing several subtypes (such as CAA). Whatever role amyloid plays, the OP is correct: correlates open interesting research avenues and this is an interesting paper if for no other reason we have few predictors of who will develop AD.

[1] https://www.nature.com/articles/s41392-023-01484-7

Can you please not post in the flamewar style? You've broken the site guidelines here and we've already had to ask you not to do that.

https://news.ycombinator.com/newsguidelines.html

Edit: actually, since your recent comments look like this, I've banned the account:

https://news.ycombinator.com/item?id=39341879

https://news.ycombinator.com/item?id=39341602

https://news.ycombinator.com/item?id=39341585

https://news.ycombinator.com/item?id=39341578

https://news.ycombinator.com/item?id=39308894

https://news.ycombinator.com/item?id=39281272

https://news.ycombinator.com/item?id=39249635

https://news.ycombinator.com/item?id=39238628

https://news.ycombinator.com/item?id=39237978

That's completely unacceptable on HN. If you don't want to be banned, you're welcome to email hn@ycombinator.com and give us reason to believe that you'll follow the rules in the future.

Thank you for all of the work you do to keep this as civil a place one could possibly expect to find that’s open to the general public on the internet.

Now is there something that can be done early or is it 15 extra years of suffering

From what I understand, the medicine available is fairly successful at staving off further disease progression but the normal late stage diagnosis often means it’s far too late. This might make outcomes significantly better if it works as well as reported.

the medicine available is just cherry picking clinical trial results to make it look better than placebo but it hardly does anything

That is true for some diseases but not all. I don't think we know how to prevent dementia. But identifying biomarkers is useful, at the very least for selecting people for enrollment in future trials.

Probably diet and exercise. Would be interesting to see an interventional study based on this.

Sleep, maybe meditation, keep learning new challenging stuff (within given cognitive possibilities).

Brain is a 'muscle' so keep pushing at it, continuously, you can only help it.

Fwiw, at least one recent study indicates there is little benefit from exercising your brain: https://www.cell.com/trends/cognitive-sciences/fulltext/S136...

related news article (in Norwegian): https://www.nrk.no/trondelag/forskning-viser-at-hjernetrim-o...

That's like weight-lifting to prevent ALS. Dementia has multiple (suspected) causes, and they are unrelated to cognitive activity. There's no evidence you can prevent plaques or cardio-vascular damage by reading or puzzling, AFAIK.

The article states there are medications that can slow or reverse the disease, if the disease is diagnosed early enough.

"An early diagnosis is critical for those with dementia. New drug technology can slow, or even reverse the progress of Alzheimer’s, but only if the disease is detected early enough. The drug lecanemab is one of two new treatments for the disease."

I wonder what kinds of useful stuff dogs can smell already… but they can’t say anything!

The most common but always impressive story I hear is that some dogs can smell cancer developing months or even a year before an official diagnosis. It honestly makes me wonder if the true next step for medical tooling should focus on enhancing human smell instead of sight to expand our spectrum or magnify microbes.

as another random trivia, many animals can often feel or hear an earthquake minutes to days in advance, demonstrated by unusual behavior. This is even less consistent but a phenomenon observed for millenia (wheras we didn't even properly name understand cancer until a few centuries at best).

> enhancing human smell

Is this not a form of spectroscopy?

Are these protein biomarkers also associated with inflammation in the body, perhaps diet-specific inflammation?

great step to figuring how we can prevent / cure these protein changes

OK, but I'd rather prevent/cure the dementia.

Is no one going to tell him? Should we?

Does this mean that big pharma can celebrate and sell more drugs?

I can't wait until we all find out it is from dentists or people picking their noses.

Why would it be from dentists?

prions "Oral manifestations are rare. Evidence suggests that the risk of transmission and acquisition of a prion infection as a result of dental treatment is rare, if appropriate infection control measures are maintained."

https://www.sciencedirect.com/science/article/abs/pii/S00028...

nose picking https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10669446/

Reply on news.ycombinator.com