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The way Alzheimer's is diagnosed is by ruling out other forms of dementia, or other diseases. There is not a direct test for Alzheimer's, which makes sense, because we don't really know what it is,

Correction here: while other tests are sometimes given to rule out additional factors, there is an authoritative, direct test for Alzheimer's: clinically detectable cognitive impairment in combination with amyloid and tau pathology (as seen in cerebrospinal fluid or PET scan). This amyloid-tau copathology is basically definitional to the disease, even if there are other hypotheses as to its cause.

> likely multiple diseases which are currently being lumped into the one label

You also described "cancer" what, 30 years ago?

We knew the symptoms, and we knew some rough classification based on where it first appeared. It took readily accessible diagnostic scans and genetic typing to really make progress.

And the brain is a lot harder imaging target.

This - it's more like an end-stage failure mode of a self-regulating, dynamic system which has drifted into dysfunction.

A case of "lots of things have to work perfectly, or near enough, or a brain drifts into this state". This seems to be very much the case with cancers, essentially unless everything regulates properly, the system would on its own devolve into cancer.

Like a gyroscope which will only spin if balanced, only this gyroscope has 10^LARGE moving parts.

And when you consider the ageing process, you're talking about multiple systems operating at 50%, 75%, 85% effectiveness, all of which interact with one another, so it's inevitable that self-regulating mechanisms start to enter failure cascade.

In terms of interventions, a lot of the time it seems like the best fix is to look at which of the critical systems is most deteriorated, and try and bring that one up. So, for example, diet and exercise can restore a degraded circulatory system by a meaningful amount, but you can be an Ironman triathlete and still develop Alzheimers in your 60s. If we can find reliable ways to do the same for sleep, that will be worthwhile, and likely there are other systems where we might do the same - immune, liver, kidneys and so on.

It sounds like corrosion in metals. There are many different damage mechanisms and protective effects, but at the end of the day you see weakened, oxidised metal.

Yes, except that metal isn't a dynamic, self-regulating structure. The body is in a constant state of actively fighting against its own decay.

Passivation is a similar kind of dynamic balance. Formation of a protective oxide layer. That's how stainless steel, aluminium don't corrode despite being pretty reactive. See also galvanized steel, which is also pretty dynamic with all the electrochemistry, transfer processes and kinetics going on.

This is spot-on. A corollary is that the best way to fight these diseases is by doing "maintenance" early on. But we currently don't have good enough models of all those multiple systems, and a functional, "good" state may vary significantly from individual to individual. Yet, those computational models could, in due time, save lives.

Be as it may, I don't believe we can create those models manually, one by one. It's just too complicated and costly, and as this article shows, prone to turf politics. The good news is that we are having great advances in molecular simulation, and there are gargantuan investments coming to develop the world's computational capabilities. Furthermore, even the current crop of AI tools is good enough to locate and make information accessible to non-experts. So, if you are looking for a hobby in front of a computer, consider given these computational problems some attention.

Yep, I neglected to consider that the system isn't just self-regulating but also self-calibrating.

Even if we can't _fix_ all those systems, getting reliable predictive/status markers would be a good start. Just being able to scan for ten or twenty blood markers and work out which aspect/s of health someone needs to focus their efforts on improving. It doesn't feel like we're a million miles from being able to do that now.

As to the multiple systems - we probably want to add hormonal and short/medium term regulatory systems to that list (being able to activate even a 40yr old's motivational/dopamine response in a 75yr old would be a significant step). And take into account that there are designed-in trade-offs (slower cellular repair in ageing bodies is very possibly an evolutionary adaptation to deal with higher cancer risk in cells with more mutation damage, for example).

You just described the exact end goal of my overall research program, if we can keep the stroke, AD, and Down syndrome + AD cohorts running. Associating blood biomarkers differentially with individual disease processes and comorbid health factors is the holy grail.

Perverse professional norms and plenty of miscreants have made it a much harder road for other dementia researchers, but it's worth keeping on, and there are so many avenues that haven't been pursued.

The sleep bit is what we are working on. We increase slow-wave delta power, increasing the effectiveness of the glymphatic system to flush metabolic waste from the brain.

There is more than a decade of research into this process, the studies I pointed at earlier are focused on older adults, which see a larger improvement than a younger population, but lots of studies in university aged subjects due to the nature of research.

We have links to more of the research papers on our website https://affectablesleep.com/research

So I absolutely think you're on the right track, but also you've got a product to sell.

Certainly piqued my interest at least, depending on price point, how long it takes to demonstrate effectiveness and so on.

If we're talking about effectiveness in AD, there are LOTS more studies to go, so I don't expect to see a result there for at least 5 years.

However, effectiveness is subjectively felt on day one (depending on your current sleep habits, it's more effective in people who are somewhat sleep deprived).

We link to a bunch of the existing research on our website, and more than just "sleep time" we can track effectiveness to biomarkers such as HRV.

So in the clinic - what we usually do is a detailed neuropsychology battery. Also a patient history, but the neuropsych does provide some quantitative measures.

If there's clear amnestic memory loss, verbal fluency decline and visualspatial processing decline, it's more probably Alzheimer's. vs. if there's other features in terms of frontaldysexecutive functioning, behavioral changes, etc, then you think FTD or possibly LBD if there's reports of early visual hallucinations.

Amyloid PETs are getting a bit better so there's that. Amyloid-negative PETs w/ amnestic memory loss are being lumped under this new LATE (Limbic-Predominant Age-Related TDP-43 Encephalopathy) but that definition always felt a bit...handwavey to me.

11-32 adults is a good pilot paper but you have to raise funding for Phase II and III trials.

Awesome clarification! Thank you.

We're not the researchers, we are developing the technology to support research. They are somewhat hamstrung with the currently available technology. There are other benefits to slow-wave enhancement, non-clinical and beyond dementia. It has been suspected this could play a role in prevention of AD, we were very suspicious (and still are a bit) that we could have a direct impact in treating AD.

Having said that, the paper that looked at people with AD saw improvement in sleep, so even if we can help them subjectively feel less exhausted, that could be a quality of life benefit, even if non-clinical.

I completely agree, that proving effectiveness in treatment is a long road, but we're going through a non-clinical use first. If the research works out, we can look into clinical use at a later date.

I want to throw something by you: what if dementia-like diseases can be linked to sleep disorders? Several papers recently have linked CSF flow through the brain during sleep (the glymphatic system), which appears to be “cleaning” the brain of waste, like the plaques seen in Alzheimers. Specifically, what if a disruption of CSF production is being impacted by, say, an imbalance of CSF precursors (like electrolytes) caused by something like a hormonal imbalance or low-grade kidney issues that don’t get picked up by normal tests? This would short-circuit the glymphatic process not allowing the body to create as much CSF as it needs. Then the brain won’t get as much cleaning as it should.

EDIT: sorry, I did not see your later reply saying that you WERE focusing on sleep disruptions! my bad. And, interesting…

It is actually and very unfortunately both.

One of the researchers we are connected to has posited that increased amyloid build up decreases the effectiveness of the glymphatic system, which is why we see lower delta power in older adults which then further reduces the ability to remove build-up. It's a vicious cycle.

We also see this with cortisol levels in under slept individuals and exacerbated in people with AD.

In response to a lack of sleep, the body increases cortisol, that increase in cortisol introduces challenges in getting good sleep, which increases cortisol.

For most of us, this isn't an issue as we get on top of our sleep within a fairly short period and sort this out, but in people with AD, there is a cortisol dysregulation, and potential a circadian issue as well.

One hypothesis why the AD paper I linked to earlier had such a huge impact on AD sufferers was because PTAS has been shown to have a 15% decrease in early night cortisol levels.

The cortisol levels were not checked in the AD subjects because it was a feasibility study, but I'll be speaking with the researchers next week, and hopefully that is the plan for the next stage research.

It's also hard to distinguish whether sleep disruptions cause AD or the other way around.

I think it's fair to say that early sleep disruptions are related to the onset of AD, and then AD itself exacerbates these issues, I commented further above.

>I fear the baby is being thrown out with the bathwater here, and we need to be very careful not to vilify the Amyloid Hypotheses, but at the same time, take action against those who falsify research.

The problem is that as many of these studies build upon each other, many other studies are tainted. A great review would be necessary to sort this mess out - but with the US research insttutions in complete disarray, we are years away from such progress.

So as a lay person with an active interest in the topic, my reading of 2) is that in the treatment group, some people showed improved sleep physiology AND improved memory, and this was attributed to the treatment, but the group as a whole did not.

If some improve, and the group average score remains unchanged, does that mean some got worse, or is it a case of the group average not being statistically significant?

What this suggests to me is that there is _surely_ a link between sleep quality and memory performance, but that whether or not the proposed treatment makes any difference - that is, whether the treatment caused the sleep improvement - is doubtful. At best it seems to be "it works moderately well for some people, and not at all for others". Am I reading it correctly?

You are reading that correctly, however, it is likely a limitation of the technology they used in the study.

Strangely, the didn't mention how they decided on stimulation volume, however, most studies will either set a fixed volume for the study, or measure the users hearing while they are awake, and then set a fixed volume for that person.

Our technology (and we're not the first to do this) adapts the volume based on brain response during sleep in real-time.

When you don't do this you risk either having the volume so low that it doesn't evoke a response, or so high that you decrease sleep depth, and don't get the correct response.

Therefore, anyone who did not get the appropriate volume would end up as a non-responder.

It is also more challenging for previously used algorithms to detect a slow-wave in older adults because the delta power is lower, so some of these participants may have had limited stimulation opportunities.

We've developed methods which improve on the state of the art, but we have not validated those in a study yet.

I feel that sleep will ultimately be the answer and the cure. Personal anecdote - one of my uncles is affected by this disease. One day, my aunt could not wake him up in the morning as hard as she tried. He would mumble and try to go back to sleep. When he finally awoke after 10 minutes of my aunt basically yelling at and slapping him, he was, in her words - "back to the man I used to know". Completely lucid and able to keep up with conversation, remembering everything etc. Two days later he was back to his old confused baseline.

Certainly pop-sci but great on this topic:

https://www.waterstones.com/book/why-we-sleep/matthew-walker...

I'm not as optimistic as you that sleep will be a cure, but I'd be very surprised indeed if sleep quality weren't preventive. (Proving this might be more difficult, though - correlation/causation).

It's almost an argument by process of elimination - why else would literally every living thing with a brain need to spend so much of its time asleep? How is it that we still don't fully know what sleep (as distinct from either rest or unconsciousness) is actually for?

Multiple studies show that night shift work is bad for the brain - and for those with a habit of working nights (probably quite a few of us on HN, from time to time), if a recreational drug made your brain feel as bad as an all-nighter can, that would surely be one you'd put in the "treat with great caution" category, no?

No doubt the glymphatic system (a central part of higher animal physiology which was only discovered in the last 25 years) has a role to play. It may be that, as with cancer, once the degenerative process gets beyond a certain point, it's hard to stop - but I'm hopeful that science will unlock a good deal of understanding around prevention over the next decade or so - even if that's not much more than an approach to sleep hygiene analogous to "eat your 5 fruit and veg a day, don't have too much alcohol or HFCS, and make sure to do a couple of sessions of cardio and a few weights every week".

> Alzheimer's is likely not a single disease but likely multiple diseases which are currently being lumped into the one label

Back at uni 25 years ago they told me the same about schizophrenia and I'm sure it's still valid.

Sometimes you do need to throw the baby with the bath water.. when you have sufficient evidence that the baby is dead lol. The amyloid hypothesis sucks ass, we have spent decades and hundreds of billions trying to make it work but we need to stop making Fetch work!

I was once very skeptical of the amyloid hypothesis, but I think the genetic evidence is very convincing. Most (all?) cases of familial early onset AD are caused by mutations that increase amyloid. And there is a rare variant of the amyloid gene that is completely protective against AD. Plus the efficacy of Leqembi.

a bit like all all tumors were lumped under the same term even though biologically they differed quite a lot at the tissue level