4 ms·

Alzheimer's disrupts circadian rhythms of plaque-clearing brain cells

201 points by gmays 1y ago

latchkey 1y ago
There has been a bunch of studies connecting Alzheimers to HSV and now this potentially connects it back? "Circadian cycles impact Herpes Simplex Virus (HSV) infection by influencing both the host's immune response and the virus's replication." Update: I'm no expert in any of this. Just thinking aloud. Would love some much smarter HN community to speak up on the topic.
- cjbgkagh 1y ago
  Are we sure on the causality here? Many people get chronic fatigue from a mono infection (EBV) and chronic fatigue has a dysautonomia componenent which has a circadian rhythm component. A lot of this stuff is bidirectionally related, forming a reinforcing loop.
- kakacik 1y ago
  What about heredity of some types of Alzheimer?
  - anon84873628 1y ago
    What you'll see repeatedly in the comments on articles like this is that Alzheimer's is more of a shared endpoint of many different root causes. Usually one person is complaining that the research is focusing on the wrong cause, or only treating symptoms, or misrepresenting the problem, etc etc. While other are defending it is important incremental understanding within one part of a very large space. (Oh and don't forget the people complaining about mouse research in the first place). What I'm learning from these articles is that Alzheimer's results when certain processes fail and negative feedback loops begin. That could be due to a genetic issue (and thus is heritable as you mention), or an immune response (and thus correlated with HSV infection), a toxin, a sleep disorder, whatever. In some cases disrupting the loop maybe be enough to restore function. In others we need to understand the unique root causes. There are many areas to explore and disentangle.
  - bookofjoe 1y ago
    The Genetics of Alzheimer Disease (2012) https://pmc.ncbi.nlm.nih.gov/articles/PMC3475404/ https://pmc.ncbi.nlm.nih.gov/articles/PMC3475404/ New insights into the genetic etiology of Alzheimer’s disease and related dementias (2022) https://www.nature.com/articles/s41588-022-01024-z https://www.nature.com/articles/s41588-022-01024-z The complex genetic architecture of Alzheimer's disease: novel insights and future directions (2023) https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00076-2/fulltext https://www.thelancet.com/journals/ebiom/article/PIIS2352-39... Towards cascading genetic risk in Alzheimer’s disease (2024) https://academic.oup.com/brain/article/147/8/2680/7685999 https://academic.oup.com/brain/article/147/8/2680/7685999
mobilejdral 1y ago
The title is a bit link-bait. It should really be "Disrupting circadian rhythms of plaque-clearing brain cells is associated with Alzheimer's" > He found that too much of YKL-40, which is linked to Alzheimer’s risk in humans, leads to amyloid build-up, an accumulation that is a hallmark of the neurodegenerative disease. There are countless studies that highlight how genetics or lifestyle and other factors that result in a reduction of estrogen signaling are associated with Alzheimer's. Estrogen, primarily activated at night decreases the expression of the YKL-40 gene. All of the known interventions, from vitamin D, Mg, to gut, choline, etc all can improve estrogen signaling, decreasing YKL-40 gene. One can end up with Alzheimer's from many different routes so interventions depend on the person. If there was a pill on the market today that would only increase the plaque-clearing all this really does is move the needle, they still have reduced estrogen signaling and the next weakest part of the system would fail such as from animpaired immune system and they will probably die of pneumonia. But we could back up and say what is the most common cause of the global reduced estrogen signaling? Often increased oxy-androgens (which increase as we age), so for example 11-ketotestosterone (11-KT) which can't convert to its estrogen form results in upregulates HSD17B2. Why do we have so much inflammation causing increased oxy-androgens from the adrenals? Senescence cells releasing inflammatory factors SASP. More time more time spent on repair resulting in identity loss and mesenchymal drift. All a fancy way of saying we get older and will probably die from whatever weakest part of the system we have genetically. Fix one thing and something else breaks instead. And for those that want to bring in the most well known genetic mutation APOE e4: APOE e4/e4 has elevated choline demands hindering estrogen signaling as well as raising HDL and lowering LDL. Low estrogen influences Cholesteryl Ester Transfer Protein, raising HDL and lowers LDL beyond what e4/e4 does by itself. With less choline and less phosphatidylcholine, it decreases GLUT1 transporters reducing glucose entering the brain. All of the above leads to an escalating amyloid plaque burden. Then reduced deep sleep and the glymphatic system cleaning is reduced too and you have Alzheimer's. The above was just from memory probably had an error, but the point is Alzheimer's is not "simple" like this article pretends.
- Obscurity4340 1y ago
  What is the word on the best current and ubiquitous prophylactics, like you said Vit D(3?)
tyre 1y ago
There was a study[0] connected to videos[1] of particular flashing that trigger plaque-clearing rhythms in the brain. Maybe placebo but my mind feels quietly clearer after watching. It could be that simply slowing down and clearing my mind for that time would do the same. [0]: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002035 https://journals.plos.org/plosbiology/article?id=10.1371/jou... [1]: https://vimeo.com/1023275135/378186db55 https://vimeo.com/1023275135/378186db55 Previous HN discussion: https://news.ycombinator.com/item?id=41942096 https://news.ycombinator.com/item?id=41942096
- monkeydreams 1y ago
  > It could be that simply slowing down and clearing my mind for that time would do the same. Certainly I could not watch this in one, unbroken, session without interruption.
  - datasink 1y ago
    Interesting. Can you describe why? I watched it a few times and wasn’t really impacted by it.
    - monkeydreams 1y ago
      Because I had two work calls and a child interrupt my viewing.
pedalpete 1y ago
Here’s a link to the paper [1]. I work in the neurotech/sleeptech space, and Alzheimer’s is one of the endpoints we’re working toward. On a first read, it seems the authors frame everything through a circadian lens. Their view is that circadian genes regulate glial function, and that when those rhythms are disrupted, clearance breaks down, inflammation increases, and amyloid accumulates, contributing to Alzheimer’s. There’s another perspective in sleep science that looks at restorative function. The physiological work of sleep like slow-wave activity and glymphatic flow which may be the driver. From that view, amyloid build-up impairs glymphatic clearance, creating a downward spiral of poorer clearance and more accumulation. Circadian timing is certainly an important modulator, but it’s not the whole story. Without EEG or even basic sleep-wake data, it’s hard to know whether the changes in circadian” gene expression reported here reflect intrinsic clock disruption or simply reduced slow-wave restorative function in these mice. I've linked to two research papers[2],[3] in AD which are working with the same principles of our work at https://affectablesleep.com https://affectablesleep.com [1] https://doi.org/10.1038/s41593-025-02067-1 https://doi.org/10.1038/s41593-025-02067-1 [2] https://doi.org/10.1016/j.jagp.2024.07.002 https://doi.org/10.1016/j.jagp.2024.07.002 [3] https://doi.org/10.1093/ageing/afad228 https://doi.org/10.1093/ageing/afad228
- alfiedotwtf 1y ago
  Just curious… I’ve been told that by getting only 2-4 hours a night increases the chance of alzheimers, but is the opposite true too - ie sleeping > 12 hours a night is not good for you too (besides PE/DVT)
  - QuantumGood 1y ago
    Oversleeping is often a sign rather than a cause of other health conditions, so get medical evaluation. (1) Increase in likelihood of stroke and coronary events are the main possible issues with long sleep. (1) https://www.health.harvard.edu/blog/are-you-getting-enough-sleep-or-too-much-sleep-and-stroke-risk-2020012918727
  - pedalpete 1y ago
    You wouldn't measure your diet based on how much time you spend chewing. So why do we think time is an appropriate measure of sleep? Sleep takes time, but time does not define the restorative function of sleep. You've probably had days where you've slept a "full" 8 hours, but can still barely drag yourself through the day. Have you also had days where after just a few hours you feel great and can take on the world? How can we all have had both of these experiences, yet we still obsess over sleep time. Sleep is about Restorative Function, the neurological processes that occur during sleep. Yes, you have been told that you need to get X amount of sleep or you will get Alzheimer's. You were also told that you needed to eat fat free foods in order to lose weight. Our understanding of sleep and the brain is about where our understanding of diet and exercise was in the 70s. We knew it was important, but we had no idea what we were talking about. I'm not recommending people sleep less than what they need. But you need to understand what YOUR needs are. A blanket "everyone needs 8 hours" is doing harm to people who require more, while leaving people who need less questioning what is wrong with them. I regularly answer questions like this on reddit, "why can't I get 8 hours sleep? So our start-up isn't focused on sleep time. We don't alter sleep time, we increase the restoratative function of sleep, in the time you get.
reissbaker 1y ago
As usual with Alzheimer's studies, this is another "breakthrough" in mice. Unfortunately, every other Alzheimer's breakthrough in mice has failed to replicate in humans, because... Mice don't get Alzheimer's. We can create mice with dementia patterns that are surface-level similar to Alzheimer's (beta amyloid plaques!), and clear the plaques and even often reverse the dementia. Unfortunately this doesn't help much of anything, since those diseases we create in mice are not Alzheimer's and appear not to actually be similar causally to Alzheimer's. All of them have failed to replicate and we have many of them. I generally wouldn't trust any Alzheimer's "breakthroughs" in mice models. The models are not accurate and have thus far had zero predictive power for actual Alzheimer's in humans.
- api 1y ago
  The same is true for life extension in mice. We can massively extend the mouse life span but it doesn’t replicate in humans. The reason there is pretty easy to grasp. Mice are a short lived more R-selected (lots of offspring, lower parental investment) species. They haven’t been heavily selected for longevity, which means there’s more low hanging fruit, more opportunities to tweak something and make a mouse live longer. Humans meanwhile are among the longest lived large mammals and are extremely K-selected (few offspring, high parental investment). That means evolution has probably already tweaked all the easy life extension related knobs in humans. Going further will require going beyond the capacities of existing mammalian physiology, which is a lot harder. Probably possible, but requires a lot deeper of an understanding of what’s happening and more radical interventions.

201 points by gmays 1y ago

There has been a bunch of studies connecting Alzheimers to HSV and now this potentially connects it back? "Circadian cycles impact Herpes Simplex Virus (HSV) infection by influencing both the host's immune response and the virus's replication." Update: I'm no expert in any of this. Just thinking aloud. Would love some much smarter HN community to speak up on the topic.

cjbgkagh 1y ago
Are we sure on the causality here? Many people get chronic fatigue from a mono infection (EBV) and chronic fatigue has a dysautonomia componenent which has a circadian rhythm component. A lot of this stuff is bidirectionally related, forming a reinforcing loop.
kakacik 1y ago
What about heredity of some types of Alzheimer?
- anon84873628 1y ago
  What you'll see repeatedly in the comments on articles like this is that Alzheimer's is more of a shared endpoint of many different root causes. Usually one person is complaining that the research is focusing on the wrong cause, or only treating symptoms, or misrepresenting the problem, etc etc. While other are defending it is important incremental understanding within one part of a very large space. (Oh and don't forget the people complaining about mouse research in the first place). What I'm learning from these articles is that Alzheimer's results when certain processes fail and negative feedback loops begin. That could be due to a genetic issue (and thus is heritable as you mention), or an immune response (and thus correlated with HSV infection), a toxin, a sleep disorder, whatever. In some cases disrupting the loop maybe be enough to restore function. In others we need to understand the unique root causes. There are many areas to explore and disentangle.
- bookofjoe 1y ago
  The Genetics of Alzheimer Disease (2012) https://pmc.ncbi.nlm.nih.gov/articles/PMC3475404/ https://pmc.ncbi.nlm.nih.gov/articles/PMC3475404/ New insights into the genetic etiology of Alzheimer’s disease and related dementias (2022) https://www.nature.com/articles/s41588-022-01024-z https://www.nature.com/articles/s41588-022-01024-z The complex genetic architecture of Alzheimer's disease: novel insights and future directions (2023) https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00076-2/fulltext https://www.thelancet.com/journals/ebiom/article/PIIS2352-39... Towards cascading genetic risk in Alzheimer’s disease (2024) https://academic.oup.com/brain/article/147/8/2680/7685999 https://academic.oup.com/brain/article/147/8/2680/7685999

mobilejdral 1y ago

The title is a bit link-bait. It should really be "Disrupting circadian rhythms of plaque-clearing brain cells is associated with Alzheimer's" > He found that too much of YKL-40, which is linked to Alzheimer’s risk in humans, leads to amyloid build-up, an accumulation that is a hallmark of the neurodegenerative disease. There are countless studies that highlight how genetics or lifestyle and other factors that result in a reduction of estrogen signaling are associated with Alzheimer's. Estrogen, primarily activated at night decreases the expression of the YKL-40 gene. All of the known interventions, from vitamin D, Mg, to gut, choline, etc all can improve estrogen signaling, decreasing YKL-40 gene. One can end up with Alzheimer's from many different routes so interventions depend on the person. If there was a pill on the market today that would only increase the plaque-clearing all this really does is move the needle, they still have reduced estrogen signaling and the next weakest part of the system would fail such as from animpaired immune system and they will probably die of pneumonia. But we could back up and say what is the most common cause of the global reduced estrogen signaling? Often increased oxy-androgens (which increase as we age), so for example 11-ketotestosterone (11-KT) which can't convert to its estrogen form results in upregulates HSD17B2. Why do we have so much inflammation causing increased oxy-androgens from the adrenals? Senescence cells releasing inflammatory factors SASP. More time more time spent on repair resulting in identity loss and mesenchymal drift. All a fancy way of saying we get older and will probably die from whatever weakest part of the system we have genetically. Fix one thing and something else breaks instead. And for those that want to bring in the most well known genetic mutation APOE e4: APOE e4/e4 has elevated choline demands hindering estrogen signaling as well as raising HDL and lowering LDL. Low estrogen influences Cholesteryl Ester Transfer Protein, raising HDL and lowers LDL beyond what e4/e4 does by itself. With less choline and less phosphatidylcholine, it decreases GLUT1 transporters reducing glucose entering the brain. All of the above leads to an escalating amyloid plaque burden. Then reduced deep sleep and the glymphatic system cleaning is reduced too and you have Alzheimer's. The above was just from memory probably had an error, but the point is Alzheimer's is not "simple" like this article pretends.

Obscurity4340 1y ago
What is the word on the best current and ubiquitous prophylactics, like you said Vit D(3?)

tyre 1y ago

There was a study[0] connected to videos[1] of particular flashing that trigger plaque-clearing rhythms in the brain. Maybe placebo but my mind feels quietly clearer after watching. It could be that simply slowing down and clearing my mind for that time would do the same. [0]: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002035 https://journals.plos.org/plosbiology/article?id=10.1371/jou... [1]: https://vimeo.com/1023275135/378186db55 https://vimeo.com/1023275135/378186db55 Previous HN discussion: https://news.ycombinator.com/item?id=41942096 https://news.ycombinator.com/item?id=41942096

monkeydreams 1y ago
> It could be that simply slowing down and clearing my mind for that time would do the same. Certainly I could not watch this in one, unbroken, session without interruption.
- datasink 1y ago
  Interesting. Can you describe why? I watched it a few times and wasn’t really impacted by it.
  - monkeydreams 1y ago
    Because I had two work calls and a child interrupt my viewing.

pedalpete 1y ago

Here’s a link to the paper [1]. I work in the neurotech/sleeptech space, and Alzheimer’s is one of the endpoints we’re working toward. On a first read, it seems the authors frame everything through a circadian lens. Their view is that circadian genes regulate glial function, and that when those rhythms are disrupted, clearance breaks down, inflammation increases, and amyloid accumulates, contributing to Alzheimer’s. There’s another perspective in sleep science that looks at restorative function. The physiological work of sleep like slow-wave activity and glymphatic flow which may be the driver. From that view, amyloid build-up impairs glymphatic clearance, creating a downward spiral of poorer clearance and more accumulation. Circadian timing is certainly an important modulator, but it’s not the whole story. Without EEG or even basic sleep-wake data, it’s hard to know whether the changes in circadian” gene expression reported here reflect intrinsic clock disruption or simply reduced slow-wave restorative function in these mice. I've linked to two research papers[2],[3] in AD which are working with the same principles of our work at https://affectablesleep.com https://affectablesleep.com [1] https://doi.org/10.1038/s41593-025-02067-1 https://doi.org/10.1038/s41593-025-02067-1 [2] https://doi.org/10.1016/j.jagp.2024.07.002 https://doi.org/10.1016/j.jagp.2024.07.002 [3] https://doi.org/10.1093/ageing/afad228 https://doi.org/10.1093/ageing/afad228

alfiedotwtf 1y ago
Just curious… I’ve been told that by getting only 2-4 hours a night increases the chance of alzheimers, but is the opposite true too - ie sleeping > 12 hours a night is not good for you too (besides PE/DVT)
- QuantumGood 1y ago
  Oversleeping is often a sign rather than a cause of other health conditions, so get medical evaluation. (1) Increase in likelihood of stroke and coronary events are the main possible issues with long sleep. (1) https://www.health.harvard.edu/blog/are-you-getting-enough-sleep-or-too-much-sleep-and-stroke-risk-2020012918727
- pedalpete 1y ago
  You wouldn't measure your diet based on how much time you spend chewing. So why do we think time is an appropriate measure of sleep? Sleep takes time, but time does not define the restorative function of sleep. You've probably had days where you've slept a "full" 8 hours, but can still barely drag yourself through the day. Have you also had days where after just a few hours you feel great and can take on the world? How can we all have had both of these experiences, yet we still obsess over sleep time. Sleep is about Restorative Function, the neurological processes that occur during sleep. Yes, you have been told that you need to get X amount of sleep or you will get Alzheimer's. You were also told that you needed to eat fat free foods in order to lose weight. Our understanding of sleep and the brain is about where our understanding of diet and exercise was in the 70s. We knew it was important, but we had no idea what we were talking about. I'm not recommending people sleep less than what they need. But you need to understand what YOUR needs are. A blanket "everyone needs 8 hours" is doing harm to people who require more, while leaving people who need less questioning what is wrong with them. I regularly answer questions like this on reddit, "why can't I get 8 hours sleep? So our start-up isn't focused on sleep time. We don't alter sleep time, we increase the restoratative function of sleep, in the time you get.

reissbaker 1y ago

As usual with Alzheimer's studies, this is another "breakthrough" in mice. Unfortunately, every other Alzheimer's breakthrough in mice has failed to replicate in humans, because... Mice don't get Alzheimer's. We can create mice with dementia patterns that are surface-level similar to Alzheimer's (beta amyloid plaques!), and clear the plaques and even often reverse the dementia. Unfortunately this doesn't help much of anything, since those diseases we create in mice are not Alzheimer's and appear not to actually be similar causally to Alzheimer's. All of them have failed to replicate and we have many of them. I generally wouldn't trust any Alzheimer's "breakthroughs" in mice models. The models are not accurate and have thus far had zero predictive power for actual Alzheimer's in humans.

api 1y ago
The same is true for life extension in mice. We can massively extend the mouse life span but it doesn’t replicate in humans. The reason there is pretty easy to grasp. Mice are a short lived more R-selected (lots of offspring, lower parental investment) species. They haven’t been heavily selected for longevity, which means there’s more low hanging fruit, more opportunities to tweak something and make a mouse live longer. Humans meanwhile are among the longest lived large mammals and are extremely K-selected (few offspring, high parental investment). That means evolution has probably already tweaked all the easy life extension related knobs in humans. Going further will require going beyond the capacities of existing mammalian physiology, which is a lot harder. Probably possible, but requires a lot deeper of an understanding of what’s happening and more radical interventions.