12 ms·

Is the Alzheimer's “Amyloid Hypothesis” Wrong? (2017)

122 points by daddy_drank 8y ago

hprotagonist 8y ago
considering that another two trials washed out since this article was written, “yes” seems an ever-more plausible and tragic answer.
- aantix 8y ago
  What does “washed out” mean? What were their conclusions?
  - Ensorceled 8y ago
    When we “washed out” our HIV clinical trial it was because we had insufficient efficacy, I.e. we couldn’t prove the new test was significantly (or any) better than existing tests (luckily also ours).
  - hprotagonist 8y ago
    Washing out means that a clinical trial is halted for lack of efficacy. It means the drug candidate in question is safe to ingest, but also doesn't work to treat the condition it was designed to treat. "work" is defined as having met or exceeded predefined clinical endpoints; e.g., "cognitive assessment improves by x% on average in a cohort of Y thousand patients", or "blood cholesterol levels reduced by Z%" or whatever. It's important and sad to note, too, that the clinical targets of most modern alzheimers drug candidates are comparatively low bars. We're not shooting for a cure, we're shooting for things like "reliably slows down cognitive decline by 6 months", and we can't even do that.
alfon 8y ago
A related article that I enjoyed: https://news.harvard.edu/gazette/story/2017/05/devastating-chain-of-events-found-in-alzheimers-path/ https://news.harvard.edu/gazette/story/2017/05/devastating-c...
User23 8y ago
Derek Lowe, of Things I Won't Work With fame, has an interesting post on the subject too: http://blogs.sciencemag.org/pipeline/archives/2018/06/22/alzheimers-and-infectious-disease-for-real http://blogs.sciencemag.org/pipeline/archives/2018/06/22/alz...
tibbon 8y ago
Sadly, no mention of microglia as a possible cause. I can't explain it myself, but someone who was close to me was researching this extensively and was often frustrated by the over-focus on amyloid.
- jayzee44 8y ago
  I agree. Microglia should be where a lot of the focus should be moving. From my limited recent research on microglia and AD, it seems that plaque build up is actually a symptom that is perhaps caused by dysfunctional microglia, which normally phagocytoze plaques when functioning properly. Microglia secrete all kinds of neurotoxins and cytokines that mediate the inflammatory response. It is highly plausible that progressive damage to microglial function induces a pathological state where the microglia become destructive to the neuronal enivronment.
exhilaration 8y ago
This comment from two months ago (when Carl Kasell died) was very interesting: it is not for want of trying. Eli Lily bet the farm and lost, and they aren’t alone. At this point, we’re beginning to think previously unthinkable thoughts like “what if the hypothesis the last 20 years of research was based on (beta amyloid plaques)is just totally wrong”. we’ve made drugs that reduce plaques. they don’t ameliorate the disease. https://news.ycombinator.com/item?id=16863945 https://news.ycombinator.com/item?id=16863945
- nonbel 8y ago
  >"we’re beginning to think previously unthinkable thoughts" What made it so previously unthinkable? AFAIK, there was a rough correlation between presence of these plaques and certain symptoms (by "rough" I mean some people with the AD symptoms have no detectable amyloid beta plaques, others without AD symptoms have a lot). Then a bunch of studies where they figured out how to get amyloid beta to kill cells in a dish or make animals sick (or at least p-hacked such). Was there ever a definitive prediction derived from this hypothesis that was then tested on new data? What is it that makes people have such strong belief?
  - jcranmer 8y ago
    Well, the hypothesis was tested on data... that data being drugs to reduce amyloid plaques, which have only recently been found to not work to ameliorate Alzheimer's. The amyloid hypothesis looks to be an open-and-shut case of "correlation does not imply causation." The problem is, we don't know what actually causes Alzheimer's, and for the longest time, the amyloid plaque correlation was the only thing that looked like it could be a cause. On top of that, actually testing these hypotheses takes a long time, especially if you take the not-unreasonable attitude that tackling them after on its onset (i.e., before it's readily detectable) may be too late.
    - nonbel 8y ago
      >"Well, the hypothesis was tested on data... that data being drugs to reduce amyloid plaques, which have only recently been found to not work to ameliorate Alzheimer's." Right now I'm not even interested in how accurate the amyloid hypothesis turns out to be[1], but as you say its only recently the the hypothesis been tested. Sure, maybe it is just hard to test it, etc. But, why did people find it "unthinkable" to consider the hypothesis was incorrect before it was ever really tested? I feel like there is a really good example of philosophy/sociology of science fail to learn from here. The problem I'm interested in isnt with the hypothesis itself, its with the seemingly unwarranted very strong belief in the hypothesis amongst the "experts". [1] When I first learned amyloids are one of the most thermodynamically favorable states of polypeptides and the cell must devote constant resources to preventing their formation, I pretty much gave 99/1 odds amyloids are a symptom instead of cause.
deleted 8y ago
[deleted]
themgt 8y ago
Frightening thought: if (at least some cases of) Alzheimer's really is something akin to "Type III Diabetes", the planet and especially the USA can expect absolutely skyrocketing numbers as today's obese adults age. [1] https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-minute-is-alzheimers-type-3-diabetes/ https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-mi... [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/
- LinuxBender 8y ago
  If T2D can be reversed with fasting (to purge the pancreas of fat), does that mean we could test things like Acetyle-L-Carnitine in larger dosages in the brain to affect T3D? Or perhaps a variant of 2-hydroxypropyl-beta-cyclodextrin? Has anyone tried experimenting in this area? Or is this a viral condition as others in the thread have mentioned? Perhaps these are not mutually exclusive?
  - trendia 8y ago
    The amyloid, T3D, and viral hypotheses still don't explain why cholesterol, obesity, air pollution, lack of sleep, and sedentary liftestyle positively correlate with Alzheimer's and high caffeine intake and regular exercise negatively correlate with it.
    - subcosmos 8y ago
      They do, if you consider the recent findings that many viruses have evolved to exploit our colesterol synthesis and transport machinery to spread, it becomes clear that many diseases of aging may have a viral cause : https://medium.com/@InfinoMe/senescence-links-between-heart-disease-genomics-and-aging-fa78bde773da https://medium.com/@InfinoMe/senescence-links-between-heart-... Rhinovirus, the cause of the common cold, binds to vLDL receptors. vLDL incidentally being the primary risk factor for cardiovascular disease https://www.ncbi.nlm.nih.gov/pubmed/12857919 https://www.ncbi.nlm.nih.gov/pubmed/12857919 Influenza requires the cholesterol transport system to bud and spread http://news.mit.edu/2017/cholesterol-helps-flu-virus-escape-through-host-cell-membrane-1120 http://news.mit.edu/2017/cholesterol-helps-flu-virus-escape-... Hepatitis C virus relies on APO-E, our favorite alzheimers gene, to flourish, and APO-E genotype predicts if you will get liver cancer from Hep-B https://goo.gl/images/Hev5ev https://goo.gl/images/Hev5ev T2D, CVD, and obesity, being characterized by hypercholesterolemia and mitochondrial dysfunction, are illnesses that are supportive of viral infections. They also promote AGE formation, which activates the innate immune system through a variety of RAGE receptors, Galectin-3 being potentially a central axis as it is also part of the senescent phenotype.
clumsysmurf 8y ago
What if Alzheimers / dementia is cause by air pollution? http://www.sciencemag.org/news/2017/01/brain-pollution-evidence-builds-dirty-air-causes-alzheimer-s-dementia http://www.sciencemag.org/news/2017/01/brain-pollution-evide... A new study also investigates air pollution's role in diabetes https://medicine.wustl.edu/news/air-pollution-contributes-significantly-to-diabetes-globally/ https://medicine.wustl.edu/news/air-pollution-contributes-si...
- t3po7re5 8y ago
  Also found this which looks at urban vs rural rates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056321/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056321/
comboy 8y ago
Somebody on HN recommended "Why do we sleep" by Matthew Walker a few weeks ago. There are references in this book strongly linking lack of sleep to Alzheimer's (diabetes too btw). Maybe somebody else can dig them up I don't have the book at hand, but I echo that previous commenter sentiment: if you are only going to read one book this year - make it this one.
- djsumdog 8y ago
  I remember that article being posted on several sites months ago, stating that sleep might clean out many of the chemicals that would otherwise lead to plaque buildup. Here's the NPR version, but if you do a search you'll find several editorials on the same study: https://www.npr.org/sections/health-shots/2013/10/18/236211811/brains-sweep-themselves-clean-of-toxins-during-sleep https://www.npr.org/sections/health-shots/2013/10/18/2362118...
- rcjones 8y ago
  Excellent book! I'm only halfway through and it's already influenced the way I treat sleep. Among the most important takeaways is that diet, exercise, and sleep are commingled (as is their effect on disease and disease progression. Diet and exercise affect sleep quality; sleep quality affects dietary cravings and the ability to exercise; and so on. When one of these three pillars (diet, exercise, sleep) is strengthened/compromised, the others may be strengthened/compromised. By simply choosing to do things during the day that will improve your sleep quality at night, you're checking many of the boxes of a healthy lifestyle.
  - amelius 8y ago
    Would you also think that this book is interesting for people with a normal sleep pattern?
    - ibeckermayer 8y ago
      I haven’t read the book cover to cover, but I’ve heard him talk and read summaries. If it’s something you’re interested in, he’s definitely an authority worth listening to. It can also be very useful to diagnose/help friends and family that might struggle more with sleep and not even realize that it’s the downstream source of their problems
djsumdog 8y ago
Is the Amyloid Hypothesis related at all to Prions? Is there any research or drug research going into Prions and Alzheimer's?
- 2bitencryption 8y ago
  seeing as the worst forms are purely hereditary, that would seem unlikely. but what do I know.
jcranmer 8y ago
I like Derek's take on it: http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-alzheimers-statement http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-... > If there is any way left to send our ourselves full-tilt into another failed amyloid trial, our pledge to you is that Lilly will find it. ... we have our beloved wall, which we shall never forsake. Higher velocity! More power! Once more into the concrete, my friends! Who’s with me?
vajrabum 8y ago
Not everybody has focused on amyloids other approaches are being explored as well. Here's one example that's focused on a bacteria: https://www.bizjournals.com/sanfrancisco/news/2018/05/31/alzheimers-disease-cortexyme-verily-infection-ad.html https://www.bizjournals.com/sanfrancisco/news/2018/05/31/alz...
reasonattlm 8y ago
The continued failure of efforts to remove amyloid by immunotherapy is provoking a lot of diversity in theory in the Alzheimer's community. This is economics 101: theorizing is cheap, running trials is expensive. Expect to see more of the cheap thing than the expensive thing. The challenge in Alzheimer's disease is most likely that it has several mechanisms that are all of similar importance to degeneration. Get rid of one of them and benefits are obscured by the others. The most likely list is amyloid aggregation, tau aggregation, neuroinflammation (covering microglial dysfunction, persistent infection), energy metabolism issues (covering mitochondrial aging, loss of capillary density, etc), and vascular dementia. So therapies are needed that can address many of these issues at once. An example is the approach of restoring drainage of cerebrospinal fluid, e.g. at Leucadia Therapeutics. That should reduce all metabolic waste in the brain by restoring a normal sink for amyloid, tau, and anything else that might be an issue along the way. The amyloid hypothesis seems unlikely to be wrong; there is extensive evidence for amyloid aggregation to cause tau aggegation to cause neurodegeneration. It just isn't the only problem: certainly vascular dementia (present to a clinical level in 30%+ of Alzheimer's patients) is severe enough to question whether it is a major problem in those trials that reduced amyloid and failed to greatly improve dementia. The other big plausible issue is that amyloid is the early stage of Alzheimer's, while tau is the later stage - so messing with amyloid levels is not the way to go for late stage, severely impacted patients. Still has to be done, but it if picking only one, then tau clearance is a better bet.
- jamesblonde 8y ago
  Good summary, but i don't agree with your analysis. The end-game will be early diagnosis of abeta over-production, IMO. You will then treat that and you won't get alzheimers. Few will transition to Tau degeneration, and it's so much harder to fix. I don't think pharma will go big on Tau like they have with abeta. The blood tests for over-production of abeta are almost here - I expect them to be routine every few years for people over 50.
dawhizkid 8y ago
When will the medical community take nutrition science seriously? Why don't medical students take courses in diet and nutrition? There is so much evidence that Alzheimer's is closely linked to lifestyle (specifically diet) and the same lifestyle changes that can stop/reverse Type II diabetes like a ketogenic diet + intermittent fasting is likely highly effective in reducing onset of Alzheimers in old age.
- bluejellybean 8y ago
  Medical students and nurses do take diet and nutrition courses. I'm in a prereq nutrition class right now...
  - dawhizkid 8y ago
    And yet the first answer to type II diabetes is insulin therapy and other drugs and not "immediately stop eating sugar and refined carbs"
    - Herodotus38 8y ago
      Actually the first answer to type II is usually metformin, unless you present initially with pretty advanced disease.
    - cfadvan 8y ago
      What makes you believe that you won’t be presented with drug therapy as well as dietary advice?
    - mrestko 8y ago
      No it isn't. The Practice Guidelines from the American Association of Clinical Endocrinologists are summarized in this PowerPoint presentation from their website.[1] It is not intended for lay consumption, but you can clearly see that there is a large emphasis on diet changes and weight loss. However, as I mentioned in another comment, the reality in practice is that many people are either unwilling or unable to change their lifestyle sufficiently to reverse the condition. Even before being diagnosed with a disease there are huge returns to regularly exercising and staying fit. You feel better, look better, have more energy, sleep better, the list continues. A doctor saying, "you need to lose weight and exercise, it could help with your diabetes," is a relatively small motivator compared with all of the other benefits. 1. https://www.aace.com/files/aace_algorithm_slides.pptx https://www.aace.com/files/aace_algorithm_slides.pptx
eganist 8y ago
Shockingly nothing anywhere in these comments about the potential ties between herpes (HSV1 specifically) and Alzheimer's: https://scholar.google.com/scholar?q=alzheimer's+hsv https://scholar.google.com/scholar?q=alzheimer's+hsv Is this a fringe theory?
- strstr 8y ago
  Only sort of fringe, a few comments link to Derek Lowe's blog post which posits an infectious cause (a different strain of herpes iirc): https://news.ycombinator.com/item?id=17444515 https://news.ycombinator.com/item?id=17444515
- IAmGraydon 8y ago
  I believe you would expect a correlation between percentage of population with HSV1 and percentage with Alzheimer’s in each country. No such correlation exists.
  - eganist 8y ago
    Some of the theories seem to hinge on HSV1 and ApoE4 (https://scholar.google.com/scholar?q=hsv1+apoe4 https://scholar.google.com/scholar?q=hsv1+apoe4) both being necessary to substantially drive up the risk. One example: https://www.sciencedirect.com/science/article/pii/S0197458006000807 https://www.sciencedirect.com/science/article/pii/S019745800... I don't currently have access, but it'd be nice if someone who did could crack into the statistics of some of these.
- tim333 8y ago
  Not sure about HSV1 but there was a lot of press recently about the discover of herpes strains, HHV6A and HHV7 in alzheimer's patients brains. As discussed here recently https://news.ycombinator.com/item?id=17366591 https://news.ycombinator.com/item?id=17366591
dsego 8y ago
What happened to aducanumab? Wasn't that promising?
shadowtree 8y ago
Well, the fight is not over yet. Biogen has Aducanumab in phIII trials. Pretty big bet for them.
- shadowtree 8y ago
  well, and their results they just published are indeed encouraging. Nice bump on their stock.
leemailll 8y ago
I only skim reading researches in Alzheimer's, a thing that I suspect is that plagues are a late stage sign for the disease. And to ameliorate it is a bit like thinking that to cure age spots can reverse aging. They are the result of the disease, not the initial factor.
EamonnMR 8y ago
There's always the Tau hypothesis (ie it could be a tauopathy.) That would not require exotic explanations like a virus or Diabetes.

122 points by daddy_drank 8y ago

considering that another two trials washed out since this article was written, “yes” seems an ever-more plausible and tragic answer.

aantix 8y ago
What does “washed out” mean? What were their conclusions?
- Ensorceled 8y ago
  When we “washed out” our HIV clinical trial it was because we had insufficient efficacy, I.e. we couldn’t prove the new test was significantly (or any) better than existing tests (luckily also ours).
- hprotagonist 8y ago
  Washing out means that a clinical trial is halted for lack of efficacy. It means the drug candidate in question is safe to ingest, but also doesn't work to treat the condition it was designed to treat. "work" is defined as having met or exceeded predefined clinical endpoints; e.g., "cognitive assessment improves by x% on average in a cohort of Y thousand patients", or "blood cholesterol levels reduced by Z%" or whatever. It's important and sad to note, too, that the clinical targets of most modern alzheimers drug candidates are comparatively low bars. We're not shooting for a cure, we're shooting for things like "reliably slows down cognitive decline by 6 months", and we can't even do that.

alfon 8y ago

A related article that I enjoyed: https://news.harvard.edu/gazette/story/2017/05/devastating-chain-of-events-found-in-alzheimers-path/ https://news.harvard.edu/gazette/story/2017/05/devastating-c...

User23 8y ago

Derek Lowe, of Things I Won't Work With fame, has an interesting post on the subject too: http://blogs.sciencemag.org/pipeline/archives/2018/06/22/alzheimers-and-infectious-disease-for-real http://blogs.sciencemag.org/pipeline/archives/2018/06/22/alz...

tibbon 8y ago

Sadly, no mention of microglia as a possible cause. I can't explain it myself, but someone who was close to me was researching this extensively and was often frustrated by the over-focus on amyloid.

jayzee44 8y ago
I agree. Microglia should be where a lot of the focus should be moving. From my limited recent research on microglia and AD, it seems that plaque build up is actually a symptom that is perhaps caused by dysfunctional microglia, which normally phagocytoze plaques when functioning properly. Microglia secrete all kinds of neurotoxins and cytokines that mediate the inflammatory response. It is highly plausible that progressive damage to microglial function induces a pathological state where the microglia become destructive to the neuronal enivronment.

exhilaration 8y ago

This comment from two months ago (when Carl Kasell died) was very interesting: it is not for want of trying. Eli Lily bet the farm and lost, and they aren’t alone. At this point, we’re beginning to think previously unthinkable thoughts like “what if the hypothesis the last 20 years of research was based on (beta amyloid plaques)is just totally wrong”. we’ve made drugs that reduce plaques. they don’t ameliorate the disease. https://news.ycombinator.com/item?id=16863945 https://news.ycombinator.com/item?id=16863945

nonbel 8y ago
>"we’re beginning to think previously unthinkable thoughts" What made it so previously unthinkable? AFAIK, there was a rough correlation between presence of these plaques and certain symptoms (by "rough" I mean some people with the AD symptoms have no detectable amyloid beta plaques, others without AD symptoms have a lot). Then a bunch of studies where they figured out how to get amyloid beta to kill cells in a dish or make animals sick (or at least p-hacked such). Was there ever a definitive prediction derived from this hypothesis that was then tested on new data? What is it that makes people have such strong belief?
- jcranmer 8y ago
  Well, the hypothesis was tested on data... that data being drugs to reduce amyloid plaques, which have only recently been found to not work to ameliorate Alzheimer's. The amyloid hypothesis looks to be an open-and-shut case of "correlation does not imply causation." The problem is, we don't know what actually causes Alzheimer's, and for the longest time, the amyloid plaque correlation was the only thing that looked like it could be a cause. On top of that, actually testing these hypotheses takes a long time, especially if you take the not-unreasonable attitude that tackling them after on its onset (i.e., before it's readily detectable) may be too late.
  - nonbel 8y ago
    >"Well, the hypothesis was tested on data... that data being drugs to reduce amyloid plaques, which have only recently been found to not work to ameliorate Alzheimer's." Right now I'm not even interested in how accurate the amyloid hypothesis turns out to be[1], but as you say its only recently the the hypothesis been tested. Sure, maybe it is just hard to test it, etc. But, why did people find it "unthinkable" to consider the hypothesis was incorrect before it was ever really tested? I feel like there is a really good example of philosophy/sociology of science fail to learn from here. The problem I'm interested in isnt with the hypothesis itself, its with the seemingly unwarranted very strong belief in the hypothesis amongst the "experts". [1] When I first learned amyloids are one of the most thermodynamically favorable states of polypeptides and the cell must devote constant resources to preventing their formation, I pretty much gave 99/1 odds amyloids are a symptom instead of cause.

deleted 8y ago

[deleted]

themgt 8y ago

Frightening thought: if (at least some cases of) Alzheimer's really is something akin to "Type III Diabetes", the planet and especially the USA can expect absolutely skyrocketing numbers as today's obese adults age. [1] https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-minute-is-alzheimers-type-3-diabetes/ https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-mi... [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/

LinuxBender 8y ago
If T2D can be reversed with fasting (to purge the pancreas of fat), does that mean we could test things like Acetyle-L-Carnitine in larger dosages in the brain to affect T3D? Or perhaps a variant of 2-hydroxypropyl-beta-cyclodextrin? Has anyone tried experimenting in this area? Or is this a viral condition as others in the thread have mentioned? Perhaps these are not mutually exclusive?
- trendia 8y ago
  The amyloid, T3D, and viral hypotheses still don't explain why cholesterol, obesity, air pollution, lack of sleep, and sedentary liftestyle positively correlate with Alzheimer's and high caffeine intake and regular exercise negatively correlate with it.
  - subcosmos 8y ago
    They do, if you consider the recent findings that many viruses have evolved to exploit our colesterol synthesis and transport machinery to spread, it becomes clear that many diseases of aging may have a viral cause : https://medium.com/@InfinoMe/senescence-links-between-heart-disease-genomics-and-aging-fa78bde773da https://medium.com/@InfinoMe/senescence-links-between-heart-... Rhinovirus, the cause of the common cold, binds to vLDL receptors. vLDL incidentally being the primary risk factor for cardiovascular disease https://www.ncbi.nlm.nih.gov/pubmed/12857919 https://www.ncbi.nlm.nih.gov/pubmed/12857919 Influenza requires the cholesterol transport system to bud and spread http://news.mit.edu/2017/cholesterol-helps-flu-virus-escape-through-host-cell-membrane-1120 http://news.mit.edu/2017/cholesterol-helps-flu-virus-escape-... Hepatitis C virus relies on APO-E, our favorite alzheimers gene, to flourish, and APO-E genotype predicts if you will get liver cancer from Hep-B https://goo.gl/images/Hev5ev https://goo.gl/images/Hev5ev T2D, CVD, and obesity, being characterized by hypercholesterolemia and mitochondrial dysfunction, are illnesses that are supportive of viral infections. They also promote AGE formation, which activates the innate immune system through a variety of RAGE receptors, Galectin-3 being potentially a central axis as it is also part of the senescent phenotype.

clumsysmurf 8y ago

What if Alzheimers / dementia is cause by air pollution? http://www.sciencemag.org/news/2017/01/brain-pollution-evidence-builds-dirty-air-causes-alzheimer-s-dementia http://www.sciencemag.org/news/2017/01/brain-pollution-evide... A new study also investigates air pollution's role in diabetes https://medicine.wustl.edu/news/air-pollution-contributes-significantly-to-diabetes-globally/ https://medicine.wustl.edu/news/air-pollution-contributes-si...

t3po7re5 8y ago
Also found this which looks at urban vs rural rates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056321/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056321/

comboy 8y ago

Somebody on HN recommended "Why do we sleep" by Matthew Walker a few weeks ago. There are references in this book strongly linking lack of sleep to Alzheimer's (diabetes too btw). Maybe somebody else can dig them up I don't have the book at hand, but I echo that previous commenter sentiment: if you are only going to read one book this year - make it this one.

djsumdog 8y ago
I remember that article being posted on several sites months ago, stating that sleep might clean out many of the chemicals that would otherwise lead to plaque buildup. Here's the NPR version, but if you do a search you'll find several editorials on the same study: https://www.npr.org/sections/health-shots/2013/10/18/236211811/brains-sweep-themselves-clean-of-toxins-during-sleep https://www.npr.org/sections/health-shots/2013/10/18/2362118...
rcjones 8y ago
Excellent book! I'm only halfway through and it's already influenced the way I treat sleep. Among the most important takeaways is that diet, exercise, and sleep are commingled (as is their effect on disease and disease progression. Diet and exercise affect sleep quality; sleep quality affects dietary cravings and the ability to exercise; and so on. When one of these three pillars (diet, exercise, sleep) is strengthened/compromised, the others may be strengthened/compromised. By simply choosing to do things during the day that will improve your sleep quality at night, you're checking many of the boxes of a healthy lifestyle.
- amelius 8y ago
  Would you also think that this book is interesting for people with a normal sleep pattern?
  - ibeckermayer 8y ago
    I haven’t read the book cover to cover, but I’ve heard him talk and read summaries. If it’s something you’re interested in, he’s definitely an authority worth listening to. It can also be very useful to diagnose/help friends and family that might struggle more with sleep and not even realize that it’s the downstream source of their problems

djsumdog 8y ago

Is the Amyloid Hypothesis related at all to Prions? Is there any research or drug research going into Prions and Alzheimer's?

2bitencryption 8y ago
seeing as the worst forms are purely hereditary, that would seem unlikely. but what do I know.

jcranmer 8y ago

I like Derek's take on it: http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-alzheimers-statement http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-... > If there is any way left to send our ourselves full-tilt into another failed amyloid trial, our pledge to you is that Lilly will find it. ... we have our beloved wall, which we shall never forsake. Higher velocity! More power! Once more into the concrete, my friends! Who’s with me?

vajrabum 8y ago

Not everybody has focused on amyloids other approaches are being explored as well. Here's one example that's focused on a bacteria: https://www.bizjournals.com/sanfrancisco/news/2018/05/31/alzheimers-disease-cortexyme-verily-infection-ad.html https://www.bizjournals.com/sanfrancisco/news/2018/05/31/alz...

reasonattlm 8y ago

The continued failure of efforts to remove amyloid by immunotherapy is provoking a lot of diversity in theory in the Alzheimer's community. This is economics 101: theorizing is cheap, running trials is expensive. Expect to see more of the cheap thing than the expensive thing. The challenge in Alzheimer's disease is most likely that it has several mechanisms that are all of similar importance to degeneration. Get rid of one of them and benefits are obscured by the others. The most likely list is amyloid aggregation, tau aggregation, neuroinflammation (covering microglial dysfunction, persistent infection), energy metabolism issues (covering mitochondrial aging, loss of capillary density, etc), and vascular dementia. So therapies are needed that can address many of these issues at once. An example is the approach of restoring drainage of cerebrospinal fluid, e.g. at Leucadia Therapeutics. That should reduce all metabolic waste in the brain by restoring a normal sink for amyloid, tau, and anything else that might be an issue along the way. The amyloid hypothesis seems unlikely to be wrong; there is extensive evidence for amyloid aggregation to cause tau aggegation to cause neurodegeneration. It just isn't the only problem: certainly vascular dementia (present to a clinical level in 30%+ of Alzheimer's patients) is severe enough to question whether it is a major problem in those trials that reduced amyloid and failed to greatly improve dementia. The other big plausible issue is that amyloid is the early stage of Alzheimer's, while tau is the later stage - so messing with amyloid levels is not the way to go for late stage, severely impacted patients. Still has to be done, but it if picking only one, then tau clearance is a better bet.

jamesblonde 8y ago
Good summary, but i don't agree with your analysis. The end-game will be early diagnosis of abeta over-production, IMO. You will then treat that and you won't get alzheimers. Few will transition to Tau degeneration, and it's so much harder to fix. I don't think pharma will go big on Tau like they have with abeta. The blood tests for over-production of abeta are almost here - I expect them to be routine every few years for people over 50.

dawhizkid 8y ago

When will the medical community take nutrition science seriously? Why don't medical students take courses in diet and nutrition? There is so much evidence that Alzheimer's is closely linked to lifestyle (specifically diet) and the same lifestyle changes that can stop/reverse Type II diabetes like a ketogenic diet + intermittent fasting is likely highly effective in reducing onset of Alzheimers in old age.

bluejellybean 8y ago
Medical students and nurses do take diet and nutrition courses. I'm in a prereq nutrition class right now...
- dawhizkid 8y ago
  And yet the first answer to type II diabetes is insulin therapy and other drugs and not "immediately stop eating sugar and refined carbs"
  - Herodotus38 8y ago
    Actually the first answer to type II is usually metformin, unless you present initially with pretty advanced disease.
  - cfadvan 8y ago
    What makes you believe that you won’t be presented with drug therapy as well as dietary advice?
  - mrestko 8y ago
    No it isn't. The Practice Guidelines from the American Association of Clinical Endocrinologists are summarized in this PowerPoint presentation from their website.[1] It is not intended for lay consumption, but you can clearly see that there is a large emphasis on diet changes and weight loss. However, as I mentioned in another comment, the reality in practice is that many people are either unwilling or unable to change their lifestyle sufficiently to reverse the condition. Even before being diagnosed with a disease there are huge returns to regularly exercising and staying fit. You feel better, look better, have more energy, sleep better, the list continues. A doctor saying, "you need to lose weight and exercise, it could help with your diabetes," is a relatively small motivator compared with all of the other benefits. 1. https://www.aace.com/files/aace_algorithm_slides.pptx https://www.aace.com/files/aace_algorithm_slides.pptx

eganist 8y ago

Shockingly nothing anywhere in these comments about the potential ties between herpes (HSV1 specifically) and Alzheimer's: https://scholar.google.com/scholar?q=alzheimer's+hsv https://scholar.google.com/scholar?q=alzheimer's+hsv Is this a fringe theory?

strstr 8y ago
Only sort of fringe, a few comments link to Derek Lowe's blog post which posits an infectious cause (a different strain of herpes iirc): https://news.ycombinator.com/item?id=17444515 https://news.ycombinator.com/item?id=17444515
IAmGraydon 8y ago
I believe you would expect a correlation between percentage of population with HSV1 and percentage with Alzheimer’s in each country. No such correlation exists.
- eganist 8y ago
  Some of the theories seem to hinge on HSV1 and ApoE4 (https://scholar.google.com/scholar?q=hsv1+apoe4 https://scholar.google.com/scholar?q=hsv1+apoe4) both being necessary to substantially drive up the risk. One example: https://www.sciencedirect.com/science/article/pii/S0197458006000807 https://www.sciencedirect.com/science/article/pii/S019745800... I don't currently have access, but it'd be nice if someone who did could crack into the statistics of some of these.
tim333 8y ago
Not sure about HSV1 but there was a lot of press recently about the discover of herpes strains, HHV6A and HHV7 in alzheimer's patients brains. As discussed here recently https://news.ycombinator.com/item?id=17366591 https://news.ycombinator.com/item?id=17366591

dsego 8y ago

What happened to aducanumab? Wasn't that promising?

shadowtree 8y ago

Well, the fight is not over yet. Biogen has Aducanumab in phIII trials. Pretty big bet for them.

shadowtree 8y ago
well, and their results they just published are indeed encouraging. Nice bump on their stock.

leemailll 8y ago

I only skim reading researches in Alzheimer's, a thing that I suspect is that plagues are a late stage sign for the disease. And to ameliorate it is a bit like thinking that to cure age spots can reverse aging. They are the result of the disease, not the initial factor.

EamonnMR 8y ago

There's always the Tau hypothesis (ie it could be a tauopathy.) That would not require exotic explanations like a virus or Diabetes.