Is the Alzheimer's “Amyloid Hypothesis” Wrong? (2017)
theatlantic.com
theatlantic.com
[1] https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-mi...
Or is this a viral condition as others in the thread have mentioned? Perhaps these are not mutually exclusive?
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
Influenza requires the cholesterol transport system to bud and spread 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
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.
There are a number of pathways that seem to be downregulated by purigenic receptors, many of which are sensitive to adenosine. Caffeine blocks adenosine receptors and blocks signaling.
What could be happening here is suppressing inflammation, since evidently purine nucleotides activate some immune cells.
I'm not trying to hand wave over anything, but it's hard to justify comparing cause of death stats from nearly 100 years ago to current era when we've made so many strides in combating some previously fatal diseases that are now routinely treatable or even preventable.
Alzheimer's sucks. Dementia sucks. I've worked for/with people with Alzheimer's and it's never pretty. I lost my own Grandfather to dementia last year. Neither is pretty, and the both do the same damage: typically the person suffering from the disease isn't even aware, but all family and close associates suffer instead. It's brutal to all involved.
https://www.npr.org/sections/health-shots/2013/10/18/2362118...
Get lots of sleep.
The book is mostly helpful for people who try to "optimize" things or rationalize why they don't need to follow the rules. He debunks all of the excuses.
If you already get enough sleep, then you don't need the book.
If you're pragmatic then increasing quality of your sleep may make it worth reading.
I’m only midway through it, but I could see how some of the material could seem redundant or sensationalized if you’re not at least somewhat interested. However, the author does a great job of summarizing studies and presenting data when something seems like it could be sensational. E.g., The heightened rates of heart attacks, car accidents, etc. the day we ‘spring forward’ and lose an hour of sleep in the U.S. for DST (whereas fewer cardiac events, accidents, etc. happen when we ‘fall back.’)
Likely not causal, however, we just know that these two lifestyle factors trigger cleanup processes in your body.
Here's an interesting paragraph, pertinent to the discussion of Alzheimer:
"As we learned ..., sleep quality - especially that of deep NREM sleep - deteriorates as we age. This is linked to a decline in memory. However, if you assess a patient with Alzheimer's disease, the disruption of sleep is far more exaggerated. More telling, perhaps, is the fact that sleep disturbance precedes the onset of Alzheimer's disease by several years, suggesting that it may be an early-warning sign of the condition, or even a contributor to it.
Following diagnosis, the magnitude of sleep disruption will then progress in unison with the symptom severity of the Alzheimer's patient, further suggesting a link between the two. Making matters worse, over 60% of patients with Alzheimer's disease have at least one clinical sleep disorder. Insomnia is especially common, as caregivers of a loved one with Alzheimer's disease will know all too well."
The author goes on to discuss the studies his team did in testing the hypothesis of amyloid buildup in the brain (particularly in the frontal lobe, which regulates your sleep) would impact the quality of sleep, and reduce NREM sleep - which is crucial for memory formation and retention.
So even if the amyloid hypothesis doesn't explain the onset of Alzheimer, there's enough evidence to claim that amyloid plaques may be associated with the loss of deep sleep, and damage your memory.
Now the most interesting part is where the author claims the opposite: that lack of sleep is correlated with amyloid buildups, as it disrupts the function of glymphatic system within the brain.
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.
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?
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.
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.
> “The government and the pharmaceutical industry have invested almost all their resources, and some of the brightest people have been in the amyloid area,” he says
Not so much unthinkable but if you speak that thought those invested may attack you in the political "grant applications have negative feedback" sense.
You see that quite a lot that when people have built careers based on hypothesis A they do not take kindly to the idea of A being wrong.
Personally, i take curcumin supplements, as it is known to bind to abeta even in the cerebrospinal fluid, then it gets cleared out over the blood brain barrier. If the abeta hypothesis is true, high dose curcumin should help delay its onset.
Another thing to do is get your genome sequenced, even with 23andme. If you have apoe4, you should, IMO, take curcumin.
>"Mice with excess beta-amyloid survived longer than the controls and had less bacteria in their brains. Mice lacking beta-amyloid (from the genetic removal of APP) died more often from infection."
https://www.nih.gov/news-events/nih-research-matters/alzheim...
> 96 participants aged between 40 and 90 over 12 months.
>In tests of verbal and memory skills, those taking the dummy pill suffered a decline in mental function after just six months that was not observed in those who took curcumin
At least it has no negative side effect and tastes good in its chicken korma form.
> "So far, the results have been dramatic. Among 4,000 people tested so far in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, researchers from the Memory and Aging Center at the University of California at San Francisco found that just 54.3 percent of MCI patients and 70.5 percent of dementia patients had the plaques.
A positive test for amyloid does not mean someone has Alzheimer’s, though its presence precedes the disease and increases the risk of progression. But a negative test definitively means a person does not have it."
https://www.washingtonpost.com/national/health-science/brain...
What they do is use a circular definition of:
Alzheimers symptoms + amyloid-beta = alzheimers disease
Alzheimers symptoms - amyloid-beta = other disease
So I don't disagree that technically "everyone with a confirmed AD diagnosis had amyloid build up", just that this is true by definition.
“If someone had a putative diagnosis of Alzheimer’s disease, they might be on an Alzheimer’s drug like Aricept or Namenda,” said James Hendrix, the Alzheimer Association’s director of global science initiatives who co-presented the findings. “What if they had a PET scan and it showed that they didn’t have amyloid in their brain? Their physician would take them off that drug and look for something else.”
For decades, diagnosing Alzheimer’s has been a guessing game, based on looking at a person’s symptoms rather than testing for definitive evidence of the brain disorder. A firm diagnosis was not possible until an autopsy was performed.
Now, a spinal tap or PET scan can detect the telltale amyloid deposits, and researchers are trying to develop a simple blood test that would do so. PET imaging can quantify the amount of amyloid and also show where it is in a person’s brain."
Also, if you are talking about the amyloid hypothesis, I think you could hardly call it "unfunded", it is probably one of the most well-funded medical hypotheses.
> '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”.'
That make sense? I mean, yes, people could have thought this before. But, by and large, they didn't spend time throwing money down those thoughts.
If I am misinterpreting that, then it is my poor reading. (I have some excuses right now, but they would be just that. :) )
To that end, the most upvoted direct response to you is a better worded version of what I was getting at. Sunken costs and changing where you are spending your money is my speculation on why things went the way they did. I don't have a solid answer for why this is so, though. At least, not one that generalizes.
To repeat what I think was the heart of your initial question: Why do people form strong beliefs? That is a very good question that I don't think anyone has a solid answer on. Just more beliefs that have strong proponents. :)
Admitting you have invested twenty years of research and you're not an inch closer- in fact you went down the wrong path entirely- would be a pretty bitter pill to swallow, both for researchers and patients.
I'm fairly certain I understand the brain well enough to know our understanding of the brain is rudimentary and there is no reason to become attached to a vague preliminary model like this "amyloid hypothesis".
The fun thing is that even if you consider the amyloid hypothesis to be false, that doesn't make any of the alternative theories any more likely to be true; in 10 years we could be seeing another big round of failures. In fact, the amyloid hypothesis could still be true, but nobody has found the right way to tackle the problem.
Its possible to act on a "working hypothesis" without it becoming anything close to "unthinkable" to consider other hypotheses. For some reason this amyloid hypothesis became well accepted and ingrained without good reason.
>"The fun thing is that even if you consider the amyloid hypothesis to be false, that doesn't make any of the alternative theories any more likely to be true"
This violates Bayes' theorem.
>"In fact, the amyloid hypothesis could still be true, but nobody has found the right way to tackle the problem."
Why don't the supporters of the amyloid hypothesis make a definitive prediction, then if it doesnt work out the hypothesis can be dropped?
This is my point. It was never literally true that alternatives were "unthinkable"; the word "unthinkable" was a small bit of hyperbole on the part of the author of the quote we have been discussing. Just don't lose sight of the fact that the amyloid hypothesis did and still does have good evidence for it. (In addition to a whole load of new and very expensive evidence against it.)
What is this evidence? The evidence I know of is quite weak. There are a few correlations here and there, and the "amyloid hypothesis" has never even yielded some kind of quantitative model to be tested. Instead it just keeps getting more and more byzantine".
I can't say personally. As commented elsewhere, I first looked into it about 2014 and almost immediately thought this amyloid hypothesis should have died years ago.
>"the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it"
This doesnt mean much to me. If thats where the funding is then people will link their research to it. If NIH is about "aging" this year then you change your grant to use "aged rats", or somehow link your study to "climate change" or whatever.
>"If you think that the evidence was so weak that everybody who worked on it is crazy, then you're wrong."
Crazy, no. Personally, I think it was a near total lack of quantitative thought. Stuff like people teaching/learning "APP and presenilin mutations are linked to Alzheimers", when it was only single digit or less percent of cases that could account for:
>"The first mutation causing the familial form of the disease was identified in the amyloid precursor protein (APP) gene on chromosome 21.8 When investigating other families with the familial disease, several additional APP mutations were found. However, these mutations explain only a few familial cases. Instead, mutations in the highly homologous presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes account for most cases of familial disease.9,10 However, the familial form of the disease is rare, with a prevalence below 0·1%.11" https://www.ncbi.nlm.nih.gov/pubmed/16876668
> This doesnt mean much to me. If thats where the funding is then people will link their research to it. If NIH is about "aging" this year then you change your grant to use "aged rats", or somehow link your study to "climate change" or whatever.
I don't mean doing research with grant money, I mean that hundreds of people at half a dozen or more companies spent billions of dollars of private funding and at least a decade of their lives to develop drugs based on the amyloid hypothesis. That means that the evidence was good enough, or the evidence for any alternatives bad enough, to speculate on. Drug development is always speculative, but it's not crazy or irrational. And it's not a lack of quantitative thought, either; it's speculation.
But my purpose here wasn't to defend the evidence (as you seem to want me to do), it was merely to point out that for all this time "the" amyloid hypothesis (again, it's a family of hypotheses because each drug has a different intended mechanism of action and is therefore a different testable hypothesis) has been the only workable theory of how the disease works. Thus someone used the word "unthinkable", which you objected to. He clearly didn't mean it literally, since people have actually thought about alternatives, so it must have been hyperbole. Since he probably agrees with you that the evidence is weak in absolute terms, I don't see why you would object to the hyperbole. I pointed it out because your question (which was "What made it so previously unthinkable?") indicated that you were taking the word literally.
Afaict, there was nothing especially workable about it vs eg the "cholinergic hypothesis". In fact the only drugs that are said to help were devised based on that hypothesis.[1] So something else is going on here.
> This violates Bayes' theorem.
Not quite. If I understand the math correctly, this would only be true if we had a complete enumeration of all the other possible theories. Since the real cause of Alzheimer's could be something nobody has thought of yet, disproving a single theory would not add significant evidence in favor of the theories we have enumerated.
Pr(H0|Data) = Pr(H0)Pr(Data|H0)/sum(Pr(H[0:n])Pr(Data|H[0:n]))
If the data indicates you lower the probability of any hypothesis 0:n, it means the others all become more likely. There is no reason this has to be by a significant amount though.
Also, "you cant do the sum, therefore its insignificant" makes no sense.
Did you read the article? Every drug manufacturer who came up with a therapy made a definitive prediction. One predicted that drug A would break down the plaques and people would recover. Disproven. Another predicted that drug B would slow down plaque formation and people would recover. Disproven. Another predicted that drug C could bind with and disable protein A which normally disables protein B which removes amyloid plaques (and thus drug C would have the effect of letting protein B work longer before getting down-regulated) and that people would recover. Disproven.
But we come back to the reason why the someone used the word "unthinkable": a lot of researchers think that whatever the cause of Alzheimer's turns out to be, it will have to explain why amyloid plaques exist in Alzheimer's patients. (If it were just a random coincidence, you would expect the plaques to show up in people without Alzheimer's, but they don't.) So everyone who disproved at great expense some theory about amyloid plaques is going to look for some related theory that they can try, since that won't require that they start from scratch. They can test early treatment, or a combination therapy, or...
I think you can see that the brain is complicated enough that "amyloid plaque in the brain causes Alzheimer's" is not quite detailed enough to test. No one has figured out how the brain works well enough to prove that the plaques cause the damage (or even to quantify in objective terms at the neural level what the damage is), and the formation and removal of plaques is a horrible web of interactions between potentially thousands of proteins. Thus every specific, testable theory ends up being quite similar to a lot of other specific, testable theories. Disproving one doesn't disprove them all.
So the best way to disprove the amyloid hypothesis might turn out to be finding a cure by some other route. The exiting thing is that people are starting to actually try this, with real money. Perhaps in 10 or 15 years we'll know if they succeeded. Or it might take longer.
I don't see what "random coincidence" has to do with it, there can be a correlation for a pretty much infinite number of reasons besides the amyloid hypothesis.
Anyway this is wrong. It seems to be that ~20-30% of "cognitively normal" elderly have substantial plaques. This increase with age. The earliest reference I found for this info was 1937:
>"there is now building data on Aβ deposition in healthy controls that suggest at least 20% and perhaps as much as a third of healthy older adults show significant deposition." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844114/
>"An attempt was made to estimate the severity of the histologic alterations as a whole, and it was found that severe intellectual impairment was apt to occur in cases showing extensive involvement. However, this parellelism was neither close or constant. There were enough exceptions to make one reject the idea that there could be any simple and direct quantitative relationship between clinical and pathologic changes.
For example, in case 4 (Table i), a patient with a paranoid type of senile psychosis, there was only a minimal amount of intellectual impairment though the changes in the brain, particularly with respect to plaques, were very extensive." https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.93.4.75...
>"There is a close relationship between the degree of dementia measured during life and quantitative neuropathological changes found post mortem, with two important exceptions: (1) brains of nondemented elderly patients sometimes contain pathological features in a degree diagnostic of Alzheimer’s disease; and (2) conversely, there are occasional brains of demented subjects that do not contain markers of Alzheimer’s disease or of other disorders known to produce dementia that can be detected by neuropathological examination. The discovery of such exceptions led some neuropathologists in the 1950s to doubt the importance of Alzheimer brain changes as a cause of dementia in the elderly 1161." https://www.ncbi.nlm.nih.gov/pubmed/2897823
>"Ten subjects whose functional and cognitive performance was in the upper quintile of the nursing home residents, as good as or better than the performance of the upper quintile of residents without brain pathology (control subjects), showed the pathological features of mild Alzheimer's disease, with many neocortical plaques. Plaque counts were 80% of those of demented patients with Alzheimer's disease." https://www.ncbi.nlm.nih.gov/pubmed/2897823
>"Recent advances in amyloid imaging have made it possible to observe Aβ amyloid accumulation in the patient's brain. As a result, it has been found that there are many normal patients with amyloid deposits, and also AD patients with very few amyloid deposits (Edison et al., 2007; Li et al., 2008). Further, in the brain of elderly non-demented patients, the distribution of senile plaques is sometimes as extensive as that of dementia patients (Davis et al., 1999; Fagan et al., 2009; Price et al., 2009; Chetelat et al., 2013)." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797629/
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.
> 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?
https://www.bizjournals.com/sanfrancisco/news/2018/05/31/alz...
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-si...
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.
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.
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.
https://www.hsph.harvard.edu/news/hsph-in-the-news/doctors-n...
Is this a fringe theory?
I don't currently have access, but it'd be nice if someone who did could crack into the statistics of some of these.
Is there any research or drug research going into Prions and Alzheimer's?
Biogen has Aducanumab in phIII trials. Pretty big bet for them.