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.
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?
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.
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-...
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
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.
You tied together a lot of threads that I've been loosely aware of here. Nice post. I hope we a have the chance to elucidate what of these links is relevant and actionable.
In the context of the infectious disease hypothesis, do you know why caffeine / coffee would be associated with lower incidence of Alzheimer's? (It reduces amyloid-beta levels, but if plaques are not the cause of Alzheimer's then this shouldn't provide any protective benefit)
It's ongoing work for me. Lately I've been digging through a lot of gene expression datasets to try and figure out which genes are the most overexpressed in aging tissues. I then use bioinformatics tools like clue.io to figure out which OTHER genes regulate them, and also possible drugs.
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.
Its not difficult to come up with mechanisms like that, not even difficult to come up with the idea and then get some evidence consistent with it. The key is to make sure everything works out quantitatively: https://www.ncbi.nlm.nih.gov/pubmed/12242150
So this theory holds for caffeine, not specifically coffee? I'm not sure why, but I was under the impression that it was specifically coffee that could be tied to lower incidence of Alzheimers.
There was some youtube where some doc connects the alzheimers of the babyboomers to heart or sugar medication, can't remember <_< too much information out there
Well, to be fair, if you eliminate the common causes of death, other, new, common causes will crop up. At the start of the babyboomer generation, small pox & polio were being wiped out, so it's natural that something else came in to take its place. Hell, cancer likely wasn't a great common killer even a century ago until people started living long enough to experience it.
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.
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.
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.
There's a lot of stuff in there, and it is very compelling, but there is really only one take-away from it:
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.
Yes, if you have any interest in sleep or the role it may play in the onset or progression of diseases like Alzheimer’s, cancer, cardiovascular issues, diabetes, etc.
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.’)
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
You're on HN. You've got a curious mind. Isn't that an interesting question? Why do we sleep? There's been some good progress on trying to answer that. It doesn't just have to be some binary answer, there's a lot going on there.
If you're pragmatic then increasing quality of your sleep may make it worth reading.
Sleep time is the only time almost everybody in modern society isn't eating/digesting something. Maybe it has some of the effects of fasting? As it is also has been noted to have good effect in treatment for Alzheimer¹ and Diabetes².
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:
+1. I made the original comment on the other thread [1], and repeat here for others: if you read only one book this year, let me strongly recommend you consider this one ("Why We Sleep").
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.
Not causal, but important to clear beta-amyloid. We've done some interesting imaging studies in our center @UCSF showing radiolabelled beta-amyloid is decreased with proper sleep and exercise. The direct imaging evidence is convincing.
Likely not causal, however, we just know that these two lifestyle factors trigger cleanup processes in your body.
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.
>"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?
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.
>"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.
Being a little cynical the reason for the "unthinkable" thing may be in the article:
> “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.
This is far from the whole story. The pathology of alzheimers as predicted by the Amyloid Hypothesis is (year 0) imbalance in the production, (year 10-30) deposition of abeta causes Tau and other downstream complications that are symptomatic. Existing clinical studies started way too late, after the appearance of significant sympthoms - at least mild cognitive impairment.
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.
Fyi, I have no idea if your regimen (or any) of curcumin is good for you or not but amyloid beta may be protective in some way:
>"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."
Curcumin won't clear out all abeta. Just bind to some and clear it. It also dampens anti-inflammatory pathways (e.g., mild inhibitor of TNF-alpha production).
I see the cost-benefit being overall positive for medium-dose curcumin (like 500mg-1g/day).
> 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.
Would you mind sharing which curcumin supplements you take? I'm currently taking one 750mg capsule of curcumin per day but I've been considering switching to theracurmin after reading about it in Hacker News comments.
I take biocurcumax. Curcumin with bioperine is also good - i wouldn't take theracurmin, though. Afaik, it has lots of downstream curcumin metabolites, and they aren't anti-inflammatory/abeta-binding.
The word "unthinkable" here is probably just hyperbole. There were other hypotheses, complete with papers published about them, but there was a lot less to support them than the amyloid hypothesis. Amyloid is simply the only obvious difference between someone suffering from Alzeheimer's and anyone else. As a result, at least half a dozen different pharmaceutical companies each spent billions to develop a therapy based on it. Since it generally takes around 10 years to develop a drug, they made those choices before a lot of the alternatives had any data to back them up. I'm no expert, but I'd be willing to bet that the recent study of the viral hypothesis couldn't even have been done 10 years ago.
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.
>"Since it generally takes around 10 years to develop a drug, they made those choices before a lot of the alternatives had any data to back them up."
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?
> 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.
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.)
>"Just don't lose sight of the fact that the amyloid hypothesis did and still does have good evidence for 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".
Yea, the evidence for it was never amazing, in absolute terms. But how much of that is hindsight? The alternative theories have even worse evidence, so the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it. If you think that the evidence was so weak that everybody who worked on it is crazy, then you're wrong. It'll take years of work before anyone has an alternative theory with as much going for it.
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
>> 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.
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.
>'"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.'
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.
> Why don't the supporters of the amyloid hypothesis make a definitive prediction, then if it doesnt work out the hypothesis can be dropped?
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.
>"(If it were just a random coincidence, you would expect the plaques to show up in people without Alzheimer's, but they don't.)"
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 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.
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.
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.
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.
So some sort of critical mass was hit after x years and if that bet was wrong they are doomed for the next 20-40? Why didn't they wait until an actual definitive prediction came true?
Nobody understand the brain well enough to do that yet. Furthermore, the existence of a cure for a disease goes a long way towards proving what the mechanism of the disease is.
>"Nobody understand the brain well enough to do that yet."
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".
It's not so vague as it might sound. There's good evidence that people with amyloid plaque build-up, in the brain or in other organs, have different versions of the genes that code for the production of amyloid proteins than people who do not.
I think the correlation was a bit different. It's my understanding not everyone with amyloid build up had symptoms, but everyone with a confirmed AD diagnosis had amyloid build up.
I quickly found this, it looks like its based off a conference presentation but know there are older sources saying about the same:
> "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."
Dementia is essentially a phenotype rather than a specific pathophysiology. (I know someone who died of a non-Alzheimer's form of dementia, specifically vascular dementia). I don't know what the exact definition of Alzheimer's is, but I believe it's based primarily on the neurodegeneration of the cerebral cortex rather than the definitive presence of amyloid buildup.
Whatever the details, they were diagnosing people and giving them "Alzheimers drugs" until they saw lack of amyloid-beta. To me it sounds like the "definitive evidence" is "telltale amyloid deposits":
“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."
More that it was unfunded. A large part of that is likely that it is difficult to fund a method nobody else is investigating. Specifically, to heavily fund it.
What was unfunded, the amyloid hypothesis? If the hypothesis was not fully investigated, it may be ok to tentatively accept it anyway. But I don't see how dropping it later became an "unthinkable thought".
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.
Apologies, I meant I was guessing the original poster used "unthinkable" where they meant "unfundable." And even there, I was expecting it to mean "largely unfundable." With little in the way of results elsewhere, it is hard to justify large spending elsewhere.
Ok, I get what you are saying now, but not how you could interpret this statement that way:
> '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”.'
I took the parent's claim to be more that most of the alternative research just didn't seem to be happening. It wasn't that people didn't think it Alzheimer's couldn't be virus/whatever related; but it was widely true that no funded research was looking into that. Instead, a large portion of the funding went into the "amyloid hypothesis."
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.
I do understand what you are taking that quote to mean. It just seems like quite a stretch to me. Or at least, if you are correct, I would not trust myself to accurately interpret anything they say.
I was taking the quote to mean that not many people were researching causes/treatments of Alzheimer's that were not related to the "Amyloid hypothesis."
If I am misinterpreting that, then it is my poor reading. (I have some excuses right now, but they would be just that. :) )
Certainly fair. I've just taken, quite heavily lately, to the principal of charity.
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. :)
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.
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.
> 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?
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.
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.
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.
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).
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.
Current medical student here. We do learn about these things but a) the science is weaker than many areas of medicine because it is much harder to do randomized controlled trials of diet and b) patients will barely take a pill once a day for their blood pressure, much less entirely change their lifestyle.
The medical community seems to take nutrition extremely seriously, but they know that they'll never be able to convince people to change what they eat.
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.
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
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
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.
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.
[1] https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-mi...
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/