And, contrary to Betteridge's Law, seems (per the conclusion of the article; not characterizing any other research that may be out there which may conflict with this article), in fact, to be responsible.
> "Responsible" is a pretty strong word (and not supported by the research).
I think "seems, in fact, to be responsible" its a pretty fair simple characterization of the conclusion of the linked article, that Alzheimers is a human-created condition with PA has its principal risk factor.
("is responsible" would be stronger than is supported, but that's not what I said.)
I would say it seems there may be some sort of correlation. There is _no_ evidence of causality. Any claim of responsibility, no matter how qualified, is not supported by this research, in my opinion.
This is from 2013. Why has it seen essentially no news coverage? I can't, for instance, easily find it on sites like Science Based Medicine; you'd think they'd have lit up over this.
It looks like this is just a correlation based on historical availability of Tylenol and related compounds in developed countries. It's not obvious from skimming that the author identifies the cause by which Tylenol allegedly causes Alzheimer's, which would be crucial in prevention (e.g. by changing Tylenol) and/or finding a cure.
This is far from my area of expertise, so please correct me if I'm wrong, but the second section looks like it does exactly that:
PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase. Peroxynitrite modifies cerebral proteins by nitrating tyrosine residues, further challenging the microglia and exacerbating the amyloid cascade. Spontaneous reinnervation, N-acetyl cysteine administration and tyrosine supplementation may attenuate the early stages of F-AD development.
I've heard that if acetaminophen were in front of the FDA today it probably wouldn't be approved at all, and certainly not over the counter -- because of the narrow therapeutic range and the risk of liver damage.
> It looks like this is just a correlation based on historical availability of Tylenol and related compounds in developed countries.
That correlation is drawn, as is a correlation between Alzheimer's (and Alzheimer's-like symptoms) and symptoms potentially related to a side effect of a prior drug for which PA is the active metabolite, which was replaced by PA in the market.
> It's not obvious from skimming that the author identifies the cause by which Tylenol allegedly causes Alzheimer's,
Both the CYTOCHROME P450 and PA AND F-AD: EARLY-STAGE CEREBRAL INJURY sections identify particular mechanisms by which PA may cause or contribute to the progression.
Probably because writing intellectually honest defenses of contemporary western medicine isn't something that SBM does. All their posts are exactly the same. If they were to cover this it would just be one or two semi-coherent paragraphs about Bayesian statistics, followed by a long rant about how even if Tylenol is dangerous it doesn't matter because some random alternative medicine practice that has nothing to do with the topic at hand is the tool of the devil.
Every time I read some book that's critical of something from modern medicine I look up what SBM has to say about it. Because after all I'm not a medical researcher, nor am I omniscient. But what I do know is that every time, without fail, SBM has written a 'debunking' of that book that has nothing to do with the actual arguments or evidence from the book.
If you like SBM then I would propose that it's because you're not reading the actual books or primary sources they're talking about. So everything they say 'sounds correct', but only because you have no basis for actually judging.
I don't read SBM, I just know they're a popular blog whose beat this story intersects. Can you find anyone that analyzed or contextualized this paper? It seems like it should have been a bombshell.
Nope this is actually the first time I've heard of this. I feel like there are enough other good reasons not to use tylenol though that this should be largely irrelevant, though sadly it's not since it's added to tons of other products.
Just another case of HN users clicking on flashy things without stopping to examine the evidence. Some more examples:
- deep brain stimulation: hundreds of upvotes here on stories about this, but then when studies come out showing that it it no better than placebo that story gets 3 upvotes on HN.
- fecal transplants for C dificile: again hundreds of upvotes for stories touting this, but then when it is found to be no better than placebo the story gets no upvotes on HN.
These are just a few examples, but I see this all the time on HN. It makes me a little disappointed in the community and thinking that perhaps I should be hanging out somewhere else instead.
That was one study. There have been a total of 2 placebo-controlled trials into fecal transplants for C.Diff AFAIK. One showed some benefit over placebo, and the other showed no difference. It looks like that link you posted has just cherry-picked the good result.
Post links. The one I posted was the most recent I found (October 2015), but most studies I saw (every one I checked, N > 5) reported distinct success for FMT in their abstracts.
[EDIT] You've posted a link now, and the article is behind a paywall. There may be a correlation between that and the fact that it didn't get any upvotes, but we'd need sizable trials to be sure. :)
I didn't realise it was a paywall. If you search for "Mixed Results for Fecal Transplant in First Randomized Trial" you'll get through the paywall.
I hate paywalls for this reason, but I didn't find any non-paywalled versions of the article -- they all just seem to cherry-pick the good result and completely ignore the other one.
Not a biologist by any stretch of the imagination, so I am asking purely out of ignorance - how does your study debunk the OP's? Yours is about NSAIDs (i.e. aspirin) decreasing the risk of Alzheimer's, OP's is about paracetamol (not an NSAID) increasing the likelihood of Alzheimers. Correct me if I'm misunderstanding something here...
GP's study includes PA (which is also known as acetaminophen) as well as NSAIDs, and finds no effect, so it is a contrary result. Calling it a preemptive debunking may be a bit excessive, but given that it is a more direct study of the relationship, it (from the abstract, at least) seems to be a reason for skepticism.
Just ask the question. The preamble and last sentence only detract from the main point: how does your study debunk the OP's? Yours is about NSAIDs (i.e. aspirin) decreasing the risk of Alzheimer's, OP's is about paracetamol (not an NSAID) increasing the likelihood of Alzheimers.
If you're misunderstanding something, don't worry, someone will set you straight.
It found aspirin most likely has a protective effect.
It found no strong evidence of any association for acetaminophen, but the 95% confidence interval on the result is pretty wide. So it doesn't entirely rule out the possibility of there being a relationship, and based on its results alone it's entirely plausible that a test with more statistical power could find that it doubles your risk of Alzheimer's disease. But it could also plausibly find that it has a mild protective effect.
Regardless of which is the case, this study still strongly challenges what's being suggested by TFA. Even a doubling of Alzheimer's risk resulting from a lifetime of acetaminophen use is nothing at all like its suggestion that Alzheimer's is a disease that was unheard of before the development of NSAIDs related to Tylenol.
>- deep brain stimulation: hundreds of upvotes here on stories about this, but then when studies come out showing that it it no better than placebo that story gets 3 upvotes on HN.
I had no idea DBS is no better than placebo, do you have a source to back it up?
Thanks for the link. I assumed that you were commenting on DBS for Parkinsonism and was a bit surprised to find people say a proven therapy does not work.
There's a strong bias in all disciplines towards "positive" results, i.e. those that demonstrate an effect. They're more exciting, and in the short term they're usually more profitable. There isn't a lot of tolerance for thorough examination. I feel like science didn't use to be this way, or at least the romantic stories I was told about science didn't go like this.
Clearly the author didn't find the results from the paper you pointed to particularly compelling. It's listed as reference 136 and mentioned several times. The last of which, "In the absence of more precise knowledge of the extents of analgesic consumption and the durations of exposure, the reliability of these reports [45, 136, 137] is open to question." Is there a reason you find the Stewart paper to be more definitive than this author suggests?
That reference talks about "gross abuse". I'm not sure exactly what quantities they were talking about, but if you take too much of anything it will cause health problems.
The Neurology article is paywalled. From the abstract:
> No association was found between AD risk and use of acetaminophen (RR = 1.35; 95% CI: 0.79-2.30), and there was no trend of decreasing risk with increasing duration of use.
Depending on the methodology (no multiple regression?) and the possible association between NSAID and paracetamol intake, there may be a smoking gun, right there :-)
>It makes me a little disappointed in the community and thinking that perhaps I should be hanging out somewhere else instead.
Please go. Please go find that perfect place where you can hang out with people who are as smart and thoughtful as you and think exactly like you do, and only upvote the correct things that you agree with. It'll be better for us all.
I would if I could find it, but I've been thinking I might need to create it myself. You make it sound like it's just my opinion. That's not what I'm talking about at all. I'm saying that I would prefer if people upvoted good science rather than spammy press releases. Is that too much to ask?
That probably is too much to ask for stories in fields where the community has a low density of specialists. Excessive claims about, say, computing are less likely to be entertained here, simply because HN has lots of users who know about computing.
We see the same thing with big news stories: often a sensational splash with tons of upvotes and comments is followed a few days later by a follow-up showing how the original story was wrong, but going largely un-noticed.
I don't think it's too much to ask, though, for substantive articles reporting debunkings and refutations to get their share of attention. We just emailed you a repost invite for the one on deep brain stimulation, and I hope you'll continue to post those as you find them. It is a valuable service to the community.
Btw, any time you (or anyone) know of a particularly good article that fell through the cracks, you should email us at hn@ycombinator.com so we can send a repost invite or put it in the second-chance pool. Some of the most interesting and popular links that have appeared on HN recently have been rescued from oblivion this way, so there's evidence that it works. We'll probably eventually add a feature to HN for people to nominate stories for a second chance this way.
Thanks, got it. Yes, it would be good to have a prominent mechanism to request a second-chance for a good article, although I can imagine it could be prone to either abuse or a lot of work on your end.
This particular submission is not a spammy press release. It's an actual paper published in an actual journal. Your refutation is another paper which found contradictory results - that doesn't mean this paper is bad science, even if it's wrong.
It's a 45 year old hypothesis that was mostly disproven over a decade ago and then rehashed 2 years ago. It certainly isn't newsworthy, and the title is way overblown.
That may be, but it's not obvious from the link, and it's not clear to me that it would have been easy to discover. "Don't pay attention to things that aren't true" doesn't work as a heuristic. "Don't pay attention to press releases" does, but it wouldn't have caught this. Can you suggest a heuristic that would have rejected this without requiring prior background knowledge or significant effort, and would have a low false positive rate?
Basically, even if this is bad science, it looks superficially like good science. "HN users paying attention to obviously bad science" seems like a substantially different problem from "HN users paying attention to superficially good science that happens to be bad".
Is it just me, or is the "ANALGESICS AS RISK FACTORS FOR F-AD: (2) EPIDEMIOLOGY" section really uncompelling and the epidemiological evidence seems to amount to a few inconsistent cross-sectional studies with no particularly large correlations like implied, and a note that both paracetamol and Alzheimer's have increased over the past two centuries or so?
I am a programming neuroscientist who studies Alzheimer's, and I would like to say that, while it is not entirely clear whether or not N-acetylcysteine will prove fruitful as a therapeutic for Alzheimer's, PA/tylenol is not the same thing as N-acetylcysteine, so the NSAID link is irrelevant in that regards. The link between these two is that N-acetylcysteine is used as a treatment for overdose of PA - because of a metabolite which is produced following high consumption of PA (NAPQI). Importantly, this link does not indicate that they have inversely correlated mechanisms of action under normal circumstances. PA may not be worth exploring further, but the understanding of N-acetylcysteine is still worth exploring. Note I do not study this myself, just putting in my two cents.
I read on Paracetamol's wikipedia page that "Paracetamol also modulates the endogenous cannabinoid system" (https://en.wikipedia.org/wiki/Paracetamol#Society_and_cultur...). Given recent studies that indicate Alzheimer's can be treated by THC (http://www.ncbi.nlm.nih.gov/pubmed/25024327), it seems that there's some kind of connection between Alzheimer's and the endogenous cannabinoid system. If that's true, then it could mean paracetamol is not really the "cause" of Alzheimer's, but rather a part of the real cause: disruption or malfunction of our brain's cannabinoid receptors. Perhaps we will finally be able to prove, scientifically and neurologically, that these receptors cannot be ignored, they play a crucial role in our survival.
Once you know enough of the basics in a field to get by as a layperson, you'll find that scientific literature is far removed from being dry and uncontroversial. There are always heretics and novel positions being advanced - most of them wrong, but all new fields and new directions start with a few heretics, and the mainstream is consistently overturned with time, to be replaced with the new consensus. Distinguishing a good speculative hypothesis from a work of overreaching fancy can be a challenge wherever you stand in the hierarchy of knowledge, and the good-looking fallacies far outnumber the seeds of tomorrow's scientific mainstream. This is why few researchers bother to spend any time on reviewing this sort of thing when there are so very many other demands on their time.
One of the SENS Research Foundation folk turned up the open access paper on paracetamol and Alzheimer's in the course of ongoing reviews of scientific literature relevant to aging, and thought it heretical enough to share as an item of interest - as a curio well outside the current consensus, not as anything to be acted on. It makes for a good read, and is well-researched, but I think that ultimately the points being made here can be explained away by the coincidence of development of medical technology, increasing longevity, and increasing wealth. When it comes down to the biochemistry, the dots aren't really joined well enough to be very compelling.
So I offer this as an example of the fact that if you go digging around, you'll find very interesting papers that are well-researched, highly speculative, and probably wrong. The author of this paper has been advancing his theory for more than a decade, evidently without gathering much support. That is all part and parcel of the scientific process.
The conclusion of the paper, that Alzheimer's is an artifact of paracetamol use, is something of a bold conclusion, and as I noted above I don't think it stands too well against Occam's razor. It is simpler to point to rising wealth driving the sedentary, high-calorie lifestyle that greatly raises the risk of suffering age-related diseases such as Alzheimer's, and note that this coincides with advances in medical technology that allow for more reliable identification of the condition, progress in other technologies that improve record-keeping and reliability in medicine, and the concurrent trend in rising life spans such that more people survive to ages in which neurodegenerative conditions become a significant risk.
I still suggest you read the paper, as you'll find that a great deal of interesting historical data is referenced therein. You'll probably learn some things that you didn't know about the history of painkillers, for example.
TLDR: Disease Foo has become more common in the past few hundred years. You know what else has become more common in the past few hundred years? Bar! Therefore, Bar causes Foo, QED.
dear correspondents, thank you all for your various comments. much as i would like to engage with you all i fear i cannot. i am in poor health and have short life expectation.
i would like to make some general comments. first, science is a serious professional activity, too important to be discussed in a trivial or superficial manner. if you want to join the debate, please read both my papers of 2014. a search engine should find them with jones alzheimer's 2014 allergy. i cannot help it if you find them too hard to follow. i see it as my job to provide new conclusions from known facts and not to give seminars.
second, open access cost me good money, in excess of £1000; quite a sum for a pensioner.
third, i cannot deal with the many misunderstandings of my work. i never suggested that acetyl cystein is an antidote for Alzheimer [ad]. neither do i accept the findings of stewart et al [1997], whose paper i criticised with good reason in the first of my 2014 papers.
fourth, paracetamol is a wholly UNTESTED drug, and for that reason needs special attention. there have been a number of reports of the harm it does to the unborn child. i would like to provide references but my home was raided while i was in hospital in the summer and ALL my notes were stolen. i have never come across a similar incident, which gives some idea of the trenchant opposition to my work.
fifth, someone aks why there has been no news coverage? because i am totally isolated here. my emails are read, my mail is often impounded, the telephone is tapped and at least one room is bugged. this is a big operation thought to be on behalf of a huge drug company to keep the whole thing under wraps.
thank you for your interest, compliments of the season, sincerely, robert jones.........
73 comments
[ 4.5 ms ] story [ 133 ms ] threadIts conclusion is: Alzheimer disease is primarily a man-made condition with paracetamol as its principal risk factor.
http://www.neurology.org/content/48/3/626.short
F-AD is primarily a man-made condition with PA as its principal risk factor."
From the Abstract ...
https://news.ycombinator.com/item?id=4842803
[1] https://en.wikipedia.org/wiki/Paracetamol_brand_names
http://www.knowyourdose.org/common-medicines/
I think "seems, in fact, to be responsible" its a pretty fair simple characterization of the conclusion of the linked article, that Alzheimers is a human-created condition with PA has its principal risk factor.
("is responsible" would be stronger than is supported, but that's not what I said.)
PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase. Peroxynitrite modifies cerebral proteins by nitrating tyrosine residues, further challenging the microglia and exacerbating the amyloid cascade. Spontaneous reinnervation, N-acetyl cysteine administration and tyrosine supplementation may attenuate the early stages of F-AD development.
That correlation is drawn, as is a correlation between Alzheimer's (and Alzheimer's-like symptoms) and symptoms potentially related to a side effect of a prior drug for which PA is the active metabolite, which was replaced by PA in the market.
> It's not obvious from skimming that the author identifies the cause by which Tylenol allegedly causes Alzheimer's,
Both the CYTOCHROME P450 and PA AND F-AD: EARLY-STAGE CEREBRAL INJURY sections identify particular mechanisms by which PA may cause or contribute to the progression.
Every time I read some book that's critical of something from modern medicine I look up what SBM has to say about it. Because after all I'm not a medical researcher, nor am I omniscient. But what I do know is that every time, without fail, SBM has written a 'debunking' of that book that has nothing to do with the actual arguments or evidence from the book.
If you like SBM then I would propose that it's because you're not reading the actual books or primary sources they're talking about. So everything they say 'sounds correct', but only because you have no basis for actually judging.
http://www.neurology.org/content/48/3/626.short
Just another case of HN users clicking on flashy things without stopping to examine the evidence. Some more examples:
- deep brain stimulation: hundreds of upvotes here on stories about this, but then when studies come out showing that it it no better than placebo that story gets 3 upvotes on HN.
- fecal transplants for C dificile: again hundreds of upvotes for stories touting this, but then when it is found to be no better than placebo the story gets no upvotes on HN.
These are just a few examples, but I see this all the time on HN. It makes me a little disappointed in the community and thinking that perhaps I should be hanging out somewhere else instead.
Citations needed.
https://news.ycombinator.com/item?id=10679067
[EDIT] You've posted a link now, and the article is behind a paywall. There may be a correlation between that and the fact that it didn't get any upvotes, but we'd need sizable trials to be sure. :)
I hate paywalls for this reason, but I didn't find any non-paywalled versions of the article -- they all just seem to cherry-pick the good result and completely ignore the other one.
"In addition, we examined use of acetaminophen...No association was found between AD risk and use of acetaminophen"
How do you think 25cf should have handled this differently?
If you're misunderstanding something, don't worry, someone will set you straight.
It found no strong evidence of any association for acetaminophen, but the 95% confidence interval on the result is pretty wide. So it doesn't entirely rule out the possibility of there being a relationship, and based on its results alone it's entirely plausible that a test with more statistical power could find that it doubles your risk of Alzheimer's disease. But it could also plausibly find that it has a mild protective effect.
Regardless of which is the case, this study still strongly challenges what's being suggested by TFA. Even a doubling of Alzheimer's risk resulting from a lifetime of acetaminophen use is nothing at all like its suggestion that Alzheimer's is a disease that was unheard of before the development of NSAIDs related to Tylenol.
Minor point: Tylenol isn't an NSAID, nor is the prior drug to which the article links Alzheimer's.
I had no idea DBS is no better than placebo, do you have a source to back it up?
> No association was found between AD risk and use of acetaminophen (RR = 1.35; 95% CI: 0.79-2.30), and there was no trend of decreasing risk with increasing duration of use.
Depending on the methodology (no multiple regression?) and the possible association between NSAID and paracetamol intake, there may be a smoking gun, right there :-)
Please go. Please go find that perfect place where you can hang out with people who are as smart and thoughtful as you and think exactly like you do, and only upvote the correct things that you agree with. It'll be better for us all.
We see the same thing with big news stories: often a sensational splash with tons of upvotes and comments is followed a few days later by a follow-up showing how the original story was wrong, but going largely un-noticed.
I don't think it's too much to ask, though, for substantive articles reporting debunkings and refutations to get their share of attention. We just emailed you a repost invite for the one on deep brain stimulation, and I hope you'll continue to post those as you find them. It is a valuable service to the community.
Btw, any time you (or anyone) know of a particularly good article that fell through the cracks, you should email us at hn@ycombinator.com so we can send a repost invite or put it in the second-chance pool. Some of the most interesting and popular links that have appeared on HN recently have been rescued from oblivion this way, so there's evidence that it works. We'll probably eventually add a feature to HN for people to nominate stories for a second chance this way.
By the way, we just put this into the second-chance pool for you: https://news.ycombinator.com/item?id=10678573.
Basically, even if this is bad science, it looks superficially like good science. "HN users paying attention to obviously bad science" seems like a substantially different problem from "HN users paying attention to superficially good science that happens to be bad".
I have a question for you, could you give me an email I could reach you at?
Hope to talk to you soon,
--------
Once you know enough of the basics in a field to get by as a layperson, you'll find that scientific literature is far removed from being dry and uncontroversial. There are always heretics and novel positions being advanced - most of them wrong, but all new fields and new directions start with a few heretics, and the mainstream is consistently overturned with time, to be replaced with the new consensus. Distinguishing a good speculative hypothesis from a work of overreaching fancy can be a challenge wherever you stand in the hierarchy of knowledge, and the good-looking fallacies far outnumber the seeds of tomorrow's scientific mainstream. This is why few researchers bother to spend any time on reviewing this sort of thing when there are so very many other demands on their time.
One of the SENS Research Foundation folk turned up the open access paper on paracetamol and Alzheimer's in the course of ongoing reviews of scientific literature relevant to aging, and thought it heretical enough to share as an item of interest - as a curio well outside the current consensus, not as anything to be acted on. It makes for a good read, and is well-researched, but I think that ultimately the points being made here can be explained away by the coincidence of development of medical technology, increasing longevity, and increasing wealth. When it comes down to the biochemistry, the dots aren't really joined well enough to be very compelling.
So I offer this as an example of the fact that if you go digging around, you'll find very interesting papers that are well-researched, highly speculative, and probably wrong. The author of this paper has been advancing his theory for more than a decade, evidently without gathering much support. That is all part and parcel of the scientific process.
The conclusion of the paper, that Alzheimer's is an artifact of paracetamol use, is something of a bold conclusion, and as I noted above I don't think it stands too well against Occam's razor. It is simpler to point to rising wealth driving the sedentary, high-calorie lifestyle that greatly raises the risk of suffering age-related diseases such as Alzheimer's, and note that this coincides with advances in medical technology that allow for more reliable identification of the condition, progress in other technologies that improve record-keeping and reliability in medicine, and the concurrent trend in rising life spans such that more people survive to ages in which neurodegenerative conditions become a significant risk.
I still suggest you read the paper, as you'll find that a great deal of interesting historical data is referenced therein. You'll probably learn some things that you didn't know about the history of painkillers, for example.
--------