5 ms·

I work in neurotech and sleep, and our focus on slow-wave enhancement has recently had 3 papers looking at the impact in Alzheimer's. I'm not a scientist or ex

I work in neurotech and sleep, and our focus on slow-wave enhancement has recently had 3 papers looking at the impact in Alzheimer's. I'm not a scientist or expert, but we do speak with experts in the field. What I've gathered from these discussions is that Alzheimer's is likely not a single disease but likely multiple diseases which are currently being lumped into the one label. 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, which is why we have the Amyloid Hypothesis, the Diabetes Type 3 hypothesis, etc etc. 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. Here's some of the recent research in sleep and Alzheimer's 1) Feasibility study with a surprisingly positive result - take with a grain of salt - https://pubmed.ncbi.nlm.nih.gov/37593850/ https://pubmed.ncbi.nlm.nih.gov/37593850/ 2) Stimulation in older adults (non-AD) shows positive amyloid response with corresponding improvement in memory - https://pmc.ncbi.nlm.nih.gov/articles/PMC10758173/ https://pmc.ncbi.nlm.nih.gov/articles/PMC10758173/

DavidSJ 2y ago
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.
caycep 2y ago
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.
- pedalpete 2y ago
  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.
- throwaway852468 2y ago
  [dead]
ethbr1 2y ago
> 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.
- Earw0rm 2y ago
  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.
  - HPsquared 2y ago
    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.
    - Earw0rm 2y ago
      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.
ulnarkressty 2y ago
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.
- Earw0rm 2y ago
  Certainly pop-sci but great on this topic: https://www.waterstones.com/book/why-we-sleep/matthew-walker/9780141983769 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".
Earw0rm 2y ago
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?
- pedalpete 2y ago
  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.
aredox 2y ago
>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.
ramraj07 2y ago
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!
- ProjectArcturis 2y ago
  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.
Nemi 2y ago
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…
- ProjectArcturis 2y ago
  It's also hard to distinguish whether sleep disruptions cause AD or the other way around.
  - pedalpete 2y ago
    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.
- pedalpete 2y ago
  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.
agumonkey 2y ago
a bit like all all tumors were lumped under the same term even though biologically they differed quite a lot at the tissue level
stef25 2y ago
> 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.

DavidSJ 2y ago

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.

caycep 2y ago

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.

pedalpete 2y ago
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.
throwaway852468 2y ago
[dead]

ethbr1 2y ago

> 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.

Earw0rm 2y ago
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.
- HPsquared 2y ago
  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.
  - Earw0rm 2y ago
    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.

ulnarkressty 2y ago

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.

Earw0rm 2y ago
Certainly pop-sci but great on this topic: https://www.waterstones.com/book/why-we-sleep/matthew-walker/9780141983769 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".

Earw0rm 2y ago

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?

pedalpete 2y ago
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.

aredox 2y ago

>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.

ramraj07 2y ago

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!

ProjectArcturis 2y ago
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.

Nemi 2y ago

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…

ProjectArcturis 2y ago
It's also hard to distinguish whether sleep disruptions cause AD or the other way around.
- pedalpete 2y ago
  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.
pedalpete 2y ago
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.

agumonkey 2y ago

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

stef25 2y ago

> 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.