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Different Brain Regions Are Infected with Fungi in Alzheimer’s Disease (nature.com)
338 points by wilder 643 days ago | hide | past | web | 155 comments | favorite



Hi, I do research using the same methods: immunohistochemistry. This was done with rabbit polyclonal antibodies. The key being polyclonal. We don't know what those antibodies are really staining. The difference, however, is intriguing.


Could you elaborate on what polyclonal means here? Does it mean that they might not have detected fungus after all, but some other thing that would activate the same antibodies?


Yeah, but that's true for monoclonals too, just a matter of degree.

A polyclonal antibody is an extraction of (usually rabbit) blood from an animal that has been insulted with the agent you'd like to detect. The extraction is enriched for antibodies. They are less reliable, because there could also be other antibodies in there. Even the antibodies that recognize what you're looking for could be a population of antibodies, each recognizing a different part (think the blind men and the elephant parable). Presumably, you have tested that a positive control of what you're trying to look for works.

A monoclonal is different. You insult a mouse with a sample of what you'd like to detect, and then resect the spleen, which contains b-cells, cells that produce the antibody. You then fuse the b-cells with a special strain of cancer cell that will immortalize the b-cell (these are called 'hybridomas'). After sorting one cell to a well, you then test to see if the cells in the well have produced an antibody that detects what you're looking for. Therefore, you can be confident that a monoclonal antibody contains only one antibody, that recognizes only one antigen.

You don't necessarily know what the antigen is that is recognized (that's called the epitope). The epitope could be, say, a piece of protein on the outside of the fungus or a different piece of protein on the outside of the fungus. It's even conceivable that even for a monoclonal there are side-reactions against things that are naturally in the sample.

And: Epitope retrieval techniques are really complicated. So figuring out exactly what epitope is recognized is not trivial.


It might be worth explaining a bit more about how antibodies are made. There are these cells called B lymphocytes, whose job is to produce antibodies. When they form, they randomise parts of the antibody genes:

https://en.wikipedia.org/wiki/V%28D%29J_recombination

As a result, every B lymphocyte makes one particular antibody that is different to every other B lymphocyte, and which recognises a different molecular pattern to every other B lymphocyte. There's a process in their development which weeds out cells which recognises patterns in your own body, leaving a population of cells which (hopefully) recognise every possible pattern which is not part of your own body.

B lymphocytes then wander round the body, looking for stuff which binds to their antibody; if they find it, they know it must be an invader, and they raise the alarm, triggering an immune response (subject to checks and balances from other parts of the immune system). As part of that, the cell which raised the alarm will proliferate, making millions of cells producing identical antibodies, which bind to the invader and mark it for destruction by other cells of the immune system.

If an invader has more than one molecular pattern (which it will - every patch on the surface of a protein is a pattern, and a bacterium will have all sorts of proteins and other things on its surface), then a corresponding number of B lymphocytes should recognise it, and proliferate in response.

So, if you insult a rabbit with your protein, you will activate all the B lymphocytes which recognise patterns on it. If you purify antibodies from its bloodstream, you will get antibodies recognising all those patterns - and any other antibodies which happen to be in the bloodstream at the time. If you isolate a single B lymphocyte its bloodstream, make it immortal, culture it, and purify the antibodies from that, you will get a single kind of antibody, recognising a single molecular pattern.

In software terms, a monoclonal is a bit like detecting spam by grepping for a single spam-specific word, and a polyclonal is a bit like doing an n-gram comparison with a corpus of known spam.


>"you can be confident that a monoclonal antibody contains only one antibody, that recognizes only one antigen"

Not sure if you really meant that since it is kind of contradicted by some later statements, but all antibodies are promiscuous. Thinking you can map one antibody to one epitope is extremely dangerous. It is a matter of quantity (affinity/avidity), not quality.


Exactly. When i did immunocytochemistry, i had more confidence in polyclonals than monoclonals. If you get a strong signal with a polyclonal, then you know that many different antibodies are all binding the same thing, so it's very likely it's your protein. If you get a strong signal with a monoclonal, that's just one antibody - so it might be your protein, or it might be some other protein that, by chance, your antibody happens to bind tightly.


As a biomedical researcher, I'm confident in calling this sloppy science. There is no quantitation of staining differences across multiple fields (to demonstrate that the images aren't hand picked), no controls with the PCR study (or even showing the results besides one in the supplement), and no demonstration that the antibodies don't bind to amyloid. Extraordinary claims require extraordinary evidence, and this wouldn't even motivate me to perform a follow up study.


I'm curious: how does something this obviously flawed get through peer review for Nature?

(I believe you that this is bad science.)

Edit: I answered my own question here: https://en.m.wikipedia.org/wiki/Scientific_Reports (Summary: It's not Nature; it's a "megajournal" affiliated with it with apparently much lower editorial standards.)


It's hard to say--peer review isn't anything magical. Three experts read a paper and provide a recommendation to the journal editor. Ultimately, it's only the journal editor who decides whether to publish something. Unfortunately, the whole process is confidential, so in most of these cases it's not possible for most people to know what happened.


Exactly. Scientific Reports (and Nature Communications) is sometimes used for papers that don't get into Nature or any of its siblings (Genetics, Methods, Protocols, Biotechnology).


Can confirm. Had a paper rejected by Nature with the suggestion to send it to Scientific Reports instead. Scientific Reports accepted it.


This may be sloppy science, but sometimes discoveries happen in very sloppy and unpredictable ways.


Definitely lots of exciting discoveries happen by accident--possibly most. But understanding what those discoveries actually are requires carefully designed experiments. In the absence of careful controls Occam's razor has to apply.


Excuse me. Science only happens in precise and predictable ways.


Scientific discovery often happens by accident, i.e. unpredictably. And when you're not expecting to discover something, you're obviously not being precise about it.

A concrete example is the accidental discovery of the cosmic microwave background radiation. If you Google "accidental discovery" you'll find hundreds of other examples.

Or, if you prefer an Asimov quote:

"The most exciting phrase to hear in science, the one that heralds new discoveries, is not 'Eureka!' but 'That's funny...'"


I think that even the "Eureka!" type of discoveries may be labeled as accidental.


What I can conclude for sure is that the upvoting/downvoting system is very imprecise, but engaging at the same time.


Yeah, just not in the actual history of science. Take the discovery of LSD for one.


I'm not a scientist and defer to your judgement as to the quality of the research method. But if there is even a remote possibility of AD being caused by or someway associated with Fungus infections than I would hope someone does follow up research that is rock solid and not sloppy.


It's hard not to exaggerate the implications of this study if fungal infection does turn out to be the cause of AD given how huge this would be for humanity. Just off the top of my head I can say this disease has effected my family (1 set of grandparents effected by this disease so far) so I'd like for the conclusion to be correct.

I guess the next step would be testing the hypothesis with more people with AD to see if it holds up and then somehow getting approval to do drug trials (and I'm sure there will be no shortage of volunteers.) I can almost see a clamouring of families trying to get their hands on anti-fungal drugs in the future in the hope that it helps their loved ones but we simply won't know if this will help until there's more data.

Hoping for a break through. It's certainly not without precedent that we find something extremely simple / obvious that turns out to be the key. On a side note: it's interesting to think that the crack pots you see writing about candidas infections being the cause of numerous hard-to-treat illnesses -might- actually be right (in a sense.)


The discovery, if corroborated by others, could indeed be huge but I'm afraid it wouldn't open up new treatment options anytime soon. Fungal infections inside the body are really really hard to treat in the first place. Add to that the blood-brain barrier which makes it very hard to treat any type of infection in the brain. https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier#Fu...

Combination of these two factors sadly means that short of major breakthroughs in fungal antibiotic research or in drug delivery to the brain, Alzheimer is not likely to suddenly become more treatable even if the fungal infection theory proves to be true.


First, there are antifungal drugs that pass the BBB, with varying efficacy:

https://www.medicine.wisc.edu/sites/default/files/domfiles/i...

Second, antifungals have positively affected AD-like symptoms, though possibly through misdiagnosis.


I should have put a disclaimer that I'm not a doctor or expert in pharmaceutical research by any means but unfortunately have had to learn a fair bit about fungal infections the hard way due to a loved one having been affected. Antifungal treatments for internal infections are long (of the order of years), can be difficult to administer (some of them can only be done via IV) of uncertain efficacy and can have serious side effects. And this is for organs that don't have to overcome the BBB.

Nonetheless, if some anti-fungal treatments do prove to be effective against alzheimer's it'll be an amazing advance in medicine. Probably at the level of a Noble prize for the researchers. I'd love to see that happen.


It's known to be pretty difficult to treat a lot of fungal infections in the CNS. The agents we have are pretty nasty, with severe side effects.


totally - but if you can effectively treat a substantial percentage, that's huge. And some effective antifungals have what many consider tolerable in the face of AD.


I'm a hacker not a doctor but I've done some research into water purification, and here is what I've learned:

The body is mostly water. The task of removing microorganisms and fungus from water has been well studied.

Science knows of effective agents which are proven to purify water of micro-organisms like bacteria and also fungus. Some of these are being utilized in public water decontamination, and others while also effective are not used because they are less cost efficient to produce.

Water purifying agents have a varying range of effectiveness and also and a varying range of toxicity to the human body. There are a couple of agents in particular however which are both well tolerated by the body and are also remarkably effective at decontaminating water.

The one which my research indicates leads the pack in this area is a white crystalline salt named Potassium Iodide, KI. KI has been used widely by both the military and by campers in portable water decontamination.

A solution of Potassium Iodide in water (known colloquially as Iodine) was a leading and apparently very effective drug during the 19th century in the United States. There are doctors today who prescribe milligram doses of KI (many many times more than the RDA) to treat a wide array of ailments but especially in dermatology. They do not typically see serious side effects although they do frequently recommend monitoring thyroid levels while utilizing higher doses.


"Airliners are mostly aluminum. Aluminum has well-understood properties, including flight. So if an airliner stops flying we can fix it by filtering out whatever impurity was responsible."

Sounds nonsensical to you? Good. Because that's about how reasonable your "the body is mostly water" thesis sounds to someone with a biomedical background.


This argument seems to be that "The body is mostly water. The task of removing X from water has been well studied. Therefore it's easy to remove X from the body". This seems to be a logical fallacy.

Let me rephrase this argument as: "The body is mostly water. The task of removing HIV from water has been well studied. Therefore it's easy to remove HIV from the body".

Just to be clear: I have no medical expertise, this is mere conjecture. But fungal infections could perhaps persist in various cells. In neurons. In spoor form. In all sorts of manifestations, where they wouldn't be affected by the same treatment that disinfects water. I don't have any expertise to say one way or the other, but I suspect that if there were a simple solution such as "just treat with Iodine, it'll kill the fungus", this discussion wouldn't be taking place.


A quick injection of Easy Off Bam! Mould Killer should fix 'em right up.


you cannot just decontaminate your body, the human body relies on beneficial microorganisms to function. without them you'd die


Remarkably KI is gentle on the body while still doing a great job purifying water of the most common foul bacteria and fungus.

This seems like it would make no sense until you stop to consider that idea that in earlier generations of man we ate on average a lot more marine plants than we do today (kelp in particular) which are rich in Potassium Iodide. People ate kelp because it was a "low hanging fruit" so to speak, easily harvested in great quantity from the sea. Perhaps the beneficial organisms in our gut evolved to tolerate KI so that populations could tolerate eating mostly seaweed.

The Japanese still eat a lot of kelp (the average japanese male ingests more than 40mg of KI daily from seaweed), and if you crunch the statistics it looks like they may have significantly less AD among their population than we do in the west: http://www.worldlifeexpectancy.com/cause-of-death/alzheimers...


Not everybody lived nearby a sea. My family is from the north west of Argentina (Jujuy). To reach the sea you have to travel a few hundred kilometers horizontally and more than one kilometer vertically, so bringing anything from the sea was very expensive.

Moreover, the iodine content of the food was very low and that's bad for your thyroid. The government mandate to add a small amount of KI to the table salt NaCl. https://en.wikipedia.org/wiki/Iodine_deficiency


Potassium iodide is not iodine; it is a compound of iodine, with the same relation to iodine that table salt (sodium chloride) has to chlorine gas, which is a chemical weapon. In fact, both potassium iodide and sodium chloride are alkali halides, compounds of the halogens iodine and chlorine, respectively. Iodine is extremely reactive and consequently toxic, not only to people, but even more so to bacteria, which is why it is useful in disinfecting water. Tincture of iodine typically contains both potassium iodide and elemental iodine, but it's the elemental iodine that does the work.

Iodine, on contact with electron donors, will rapidly reduce them and ionize to the same nontoxic iodide found in potassium iodide, rendering it nearly harmless. However, oxidizing your body cells causes chemical burns by killing them; oxidizing bacteria and fungi kills their cells too. Pure iodine will blister your skin on contact.

Essentially your optimism arises from confusing two related, but very different, substances. Don't feel bad; I've made similar errors any number of times. One out of every ten thousand times that you think you've found an easy way to hack around a difficult and important problem, it's a breakthrough. The other 9,999 times, you're overlooking a fundamental reason your idea won't work.

It's deeply unfortunate that HN is not the kind of place that people will correct your mistakes, as I've done above, instead of silently downvoting you.

If you are using CNS stimulants (amphetamines, methylphenidate, modafinil, cocaine, maybe even caffeine) you might want to cut down your dosage. The hyperfocus they facilitate can be counterproductive when it causes you to overlook your errors and get overexcited over a possible breakthrough. This can blossom into full-blown amphetamine psychosis, which is not an experience I recommend, especially for the people around you.

A useful tool in discovering errors like this is investigating consequences that would ensue should your reasoning turn out to be true. For example:

* Potassium iodide is a chemical that people have been dosed with many times, including soldiers under controlled conditions. If it cured everything from jock itch to acute bacterial meningitis, probably someone would have noticed.

* Bottles of iodine are labeled "for external use only". If it were nontoxic, it would not be labeled in this way.

* Many potassium iodide vendors and customers are enthusiastic promoters of colloidal silver, which actually is a broad-spectrum antimicrobial that is fairly nontoxic to human bodies. (By itself, it's not effective enough to disinfect water with, but in combination with the more toxic copper, ionized silver has been used to disinfect water.) If KI were effective for disinfection, they would be promoting it as such.

* Our bodies use iodide in certain thyroid hormones, so there are enzymes devoted to moving iodide ions around, keeping them from reacting with the wrong things, etc. This is different from e.g. lead, mercury, or tellurium, which have no known biological function and cause toxicity by acting as poor substitutes for other atoms. If iodide were nontoxic and effective at stopping fungal infections, we would have evolved to concentrate it in our bodies and direct it to areas suffering from inflammation. But we didn't.


Eat a kilogram of potassium iodide and see what happens.

SPOILER: . . . . . You will die of hyperkalaemia


Would the recent discovery of lymphatic tubes going into our brains[1] be a potential area of focus for potential treatment?

[1]https://news.ycombinator.com/item?id=9647253


The article is not 100% clear, but I think the flux in the lymphatic tubes goes from the brain to outside, as in the other organs. So it will not be useful to send medicine inside the brain.

The article describe an alternative theory for Alzheimer

> In Alzheimer’s, there are accumulations of big protein chunks in the brain. We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.


Could you be more specific about the timeline? I remember when people said there was nothing that could ever be done for people with HIV. My guess is that if you know a precise cause, you'll have some basic treatments within a decade and an effective "cure" within two decades.


According to your link, there is a possibility that some cases of Alzheimers are caused by a degraded blood-brain barrier, which might also allow for fungal infections to take hold more readily.


Coconut oil seems to have benefits in Alzheimer's patients [1]. It also has anti-fungal properties. Worth a look.

[1] http://www.alz.org/alzheimers_disease_alternative_treatments...


There is no need for drugs to cross blood-brain barrier. If antifungal treatment is effective, drugs can be delivered directly to brain although that may need new series of research.


>clamouring of families trying to get their hands on anti-fungal drugs in the future in the hope that it helps their loved ones but we simply won't know if this will help until there's more data.

It may not be so hard to get data - try anti-fungals and see if the patients get better. There are plenty of patients and the drugs could be tried in countries other than the US. It could be possible to get data in a few weeks rather than years of trials.

There seem to be about a dozen anti-fungals at the moment which could be tried. Presumably the best choice would depend on which fungi was involved. http://www.ncbi.nlm.nih.gov/pubmed/17381184


> try anti-fungals and see if the patients get better

I got the impression that the disease symptoms result not from the mere presence of the fungus, but from progressive damage over a long time. So, if you don't start to treat until there are symptoms, you could kill the fungus and at best, the person would not get worse. Which is not to be dismissed, but...


It's hard to know till you try it but the experiment seems easy to do and reasonably low risk - the risk from anti-fungals is probably less of a worry than dying from Alzheimer's. So it seems worth giving it a shot even if the probabilities of success are low. The nervous system seems to have some recovery abilities, more from retraining surviving neurons than growing new ones.


>So, if you don't start to treat until there are symptoms, you could kill the fungus and at best, the person would not get worse. Which is not to be dismissed, but..

It's "not to dismissed"? It's the difference between life and death!


I bet if they double stain with anti-amyloid-Beta they will see the staining overlap. They just say they used "antibody raised against proteins obtained from C. glabrata, C. famata, C. albicans, P. betae and S. racemosum", so they don't even know (or want to say) what these antibodies react with...

Amyloids have generic secondary structure (can be created from any amino acid sequence under the right conditions) and yeast produce amyloids. They quite possibly raised antibodies towards yeast amyloids and then stained human amyloids. It is strange they do not report staining these brains for amyloid-Beta, it is an obvious thing to do.


Do the amyloid proteins you'd expect concentrate in similarly-shaped groupings? One claim is that the shape of the stains has fungal morphology. If Amyloid-beta concentrations can have fungal morphology then I would think that might strengthen your claim and weaken the paper's. I'm only an engineer though, so feel free to dismiss me as ignorant of your field. Either way I can see how these findings are not terribly interesting.


>"One claim is that the shape of the stains has fungal morphology. If Amyloid-beta concentrations can have fungal morphology then I would think that might strengthen your claim and weaken the paper's."

The evidence in the paper consists of a few representative pictures. I have never seen human brain stained for amyloid-beta, but if it stained at all I would bet lots of money that I could find at least one clump with "fungal morphology".

Also, ruling out the other explanations (such as they stained for amyloid) is not the audience's job, it is their job. They are the ones with access to the most detailed information, putting them in the best position to think about various explanations for what could be going on.


I was thinking if this is real then there must have been past cases of people with Alzheimer’s having been given antifungals for other reasons and having gotten better. Googling randomly I came across one, sadly paywalled but from the abstract the guy had been diagnosed with Alzheimer's for three years, then they figured it was cryptococcal meningitis and gave antifungals and four months later he was normal.

The interpretation in the paper was it was a misdiagnosis rather than an Alzheimer's cure but you never know.

http://content.iospress.com/articles/journal-of-alzheimers-d...



Thanks


Another recent discovery, that of the existence of a meningeal lymphatic system, makes this finding all the more interesting. As far as I know, fungus is in the set of foreign bodies that the adaptive immune system does the least about. Instead, the body mostly removes fungus by mechanical lymphatic clearance.


All of the Alzheimer's patients were 79 or older, while all of the control patients were younger than 79 except for one. More than half of the control patients were under 60. That doesn't seem like a very good control to me.


Perhaps but the discovery is still significant. Until now there was no such correlation with Alzeimher's and Fungi.

This has significant implications in terms of direction of future research.


> Until now there was no such correlation with Alzeimher's and Fungi.

The point of the criticism seems to be that with an improper control group, there still isn't such a correlation, just a suggestion of a possibility of a correlation. But it might be a correlation between, e.g., age and fungal infection.

That's why, but for the variables under study, you want your control group to look as much like your experimental group as possible.


A general correlation between age and fungal infection might be even more significant, since that suggests a path to reduce the effects of aging in general. Either way, a follow-up study to remove those control flaws and hone in on the cause would be necessary.


Even with an improper control group, the fungi-Alzheimer's correlation still exists. There may be another factor which is causing the correlation (a so-called 'dreaded third thing'), and the correlation may not indicate causation, but the correlation still exists.


That's not how correlations work.


That is how correlations may not work, though.


The improper control means that there is a just as strong of a correlation between age and fungi.


So, turns out there's many types of fungus that affect behavior, and there are even a few that create entirely new behaviors. One such example is ants, when infected by a type of fungus, will climb high and latch onto a branch by biting hard into it. This is so that the ant will get eaten by birds, which then complete the life cycle of that fungus.

There's not many well understood systems (the other well-studied one is toxoplasmosis and cats), but one researcher on Experiment, Charissa de Bekker, just released a new paper with findings from her project.

The results gave a first clue about the many genes that are involved in this manipulated biting behavior. For instance, that the fungus is likely producing LSD-like compounds and is secreting proteins that could affect serotonin and dopamine levels in the brain, as well as the ant’s ability to communicate through chemosignals with their nest mates. As well, in the paper, they release the entire transcriptome taken from the brains of these ants, giving other scientists a chance to use this as a model system and to begin to target which genes go on to influence behavior.

I was just talking to her about it this week, and so this news is very timely and a bit eerie. But very cool.

http://www.biomedcentral.com/content/pdf/s12864-015-1812-x.p...


If it turns out to be the cause too (maybe similar to cervical cancer), it's a huge discovery.

Asimov's book on science history is an interesting read, full with similar discoveries that were ignored for many years.

http://www.amazon.com/Far-Human-Eye-Could-See/dp/155817107X


I wonder how many mental illnesses are the result of imbalances in foreign organic matter/microbes/fungi/dietary issues and not issues fundamental to the brain itself?



Thanks for all of the sources. I remember listening to a talk on NPR about the same subject a while back in my car but I couldn't find a link to it.



Schizophrenia is an interesting one showing a very high correlation with antibodies for a retrovirus called HERV-W which became part of the DNA of our pre-human ancestors about 60 million years ago and which has been passed down ever since.

http://discovermagazine.com/2010/jun/03-the-insanity-virus


Exactly, we have lots of instances of other parts of the body becoming infected but brain sicknesses I think go untreated probably because they are hard to detect and the brain is so resilient.


I think it's a combination of it being difficult/expensive to get inside the brain, limiting such exploration to only the most severe cases, and also a latent bias in western culture to buy into Mind-Body Duality. The idea that the Mind is separate from the Body is still prevalent, and has an insidious effect on many people's judgement: even people who are trained otherwise.


>Therefore, 100% of the AD patients analysed thus far by our laboratory present fungal cells and fungal material in brain sections.

>No fungal material was observed in brain tissue from ten control individuals, whereas fungal infection was clearly present in brains from ten additional AD patients.

So 100% correlation so far - pretty impressive results.

I wonder about my dad who has an unexplained Parkinson's like nervous deterioration.


"Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi."


Methylene Blue has shown promise as an alzheimer's treatment. It's a potent antifungal. It easily diffuses through the blood brain barrier. It also happens to be cheap and unpatentable.


Wow sounds like a major breakthrough. How did they not notice this before?


It took thirty years for the medical establishment to accept the hypothesis that the bacteria H. pylori was the cause of peptic ulcer disease, rather than excess stomach acid.


Yeah, but that was in 1982.


Are you implying that doctors have become more accepting of theories which challenge the status quo? Do you have any reason to believe things have gotten better?

Doctors still seem to prescribe blood pressure medication and low-salt diets to people with hypertension, depite the overwhelming number of studies which show that neither prescription has any impact on mortality rates. It doesn't look like they are particularly evidence-driven or self-aware as a profession.


Doctors are selected and trained to memorize insane amounts of facts, and how to match symptoms to facts. Updating those facts is hard since they're stored when the brain is young and still great at learning (there are refresher courses doctors are required to attend to keep their accreditation, but they lean heavily towards learning new facts, not changing existing ones).


Most doctors are constantly learning new information. It's not just refresher courses, you have to pass frequent and comprehensive examinations to stay board-certified.

I have no idea why HN has this bias against physicians.


Frequent = a test every ten years in internal medicine and some continuing education/maintenance of certification. Even that is under attack (http://knowledgeplus.nejm.org/abim-moc-petition-reveals-deba...).

Doctors are human and some are constantly learning new information while others aren't. There are a lot of pressures on them that are perhaps orthogonal to "learning new things" and "keeping up with the best evidence."


Personal experience with physicians has been my primary way to gain this bias against physicians.

You could also do research on, say, Lister or checklists and get the bias that way.


You are probably right, but it is not clear which category this finding of a fungus-Alzheimer's correlation would be in. Most theories could retroactively be put in to either category (new facts or changed facts), so I am not sure whether this framework gets you anywhere.

In any case, the relative difficulty of updating previous beliefs does not excuse the failures of doctors which cause a great deal of death and suffering. When engineers fail to update their beliefs, and people die, it is called negligence.


This doesn't apply as cleanly to research, however, where the whole point is to discover new facts.


Well, medical researchers aren't doctors (they can't proscribe medication or perform medical procedures).


No impact? What about the SPRINT study ("Will lower blood pressure reduce the risk of heart and kidney diseases, stroke, or age-related declines in memory and thinking?" - 'largest study ever') was discontinued when it 'produced significant results' with the risk of death down by almost a quarter? I presume that blood pressure lowering was effected by drugs. Please clarify your comment because on the face of it (I have no expert knowledge, you may have) it seems to be quite wrong.


You are mistaken. There is very compelling evidence that controlling hypertension reduces mortality.


Hypertension is correlated with mortality, but reducing blood pressure does not seem to improve patient outcomes.


Most evidence does not suggest this.

2015: "[...] the NIH made the bold announcement that intensive intervention with a combo of three drugs to reach a new target systolic blood pressure of under 120 mm Hg reduced the rate of heart attacks, heart failure and stroke by 30% and cardiovascular deaths by 25%, "

http://www.healthnewsreview.org/2015/09/nih-sprint-study-spa...

http://www.cochrane.org/CD000028/HTN_blood-pressure-lowering...

http://eurheartj.oxfordjournals.org/content/early/2012/04/16...

http://www.escardio.org/The-ESC/Press-Office/Press-releases/...

There's more evidence available.


Contrary evidence is available, and there is no clear reason for the confusion.[1]. I have not read any of the studies you cite, though I will take a look as soon as I have the time. From what I have read, blood pressure reducing medication has been shown to reduce blood pressure (at the cost of severe side effects), but not reduce mortality.

[1] http://m.openheart.bmj.com/content/1/1/e000048.full


Your single link talks about mild hypertension, and says that interventions may not make any difference to health outcomes.

But you can look at what guidance for doctors is to compare what happens. Here's UK guidance.

https://www.nice.org.uk/guidance/cg127/chapter/Key-prioritie...

Offer drugs to people with stage one but only if there are other symptoms; offer drugs to anyone with stage two (but do careful measuring to ensure they actually have stage two); investigate causes and provide support.

It's pretty frustrating that you misrepresent the research, and what doctors do with that research, to push some anti-doctor spin.

There's plenty of bad stuff that doctors actually do.


No not Doctors, I am not dismissing the possibility of an oversight, but there are many things that got orders of magnitude better in 35 years (So, yes I have reason to believe things got better). We have much better imaging and analysis technology, much faster spread of information, 10000x faster computers etc. Considering all these, and many teams working on this problem for years, I am a bit skeptical.


what is the blood pressure data you are using to say that?


That seems to be the case as far back as medical history goes. New discoveries are sometimes dismissed or even laughed at by the establishment. Perhaps the skepticism is for good reason because there's so much quackery out there. But it seems that new medical ideas take a huge amount of effort to gain acceptance - even today.


They still haven't decided for sure if dietary cholesterol is bad for you, or salt for that matter.

The best minds of our generation are too busy selling ads to be bothered with trivial stuff like this.


As someone busy working on selling ads, I can't tell whether I should appreciate or resent this comment...


You should quit.


Thanks for telling us how you think other people should be spending their lives. That's super valuable!

(For the record, work in healthcare, but no doubt am wasting my time saving the wrong lives.)


If Alzheimer's Disease (AD) is caused by fungal infection, why have antifungals (often given for people with invasive fungal disease) never cured an AD patient? AD is common enough that many of these people will have received antifungals for e.g. esophageal thrush or even fungemia.

Regarding the research, the data presented here are not convincing without larger scale replication with better controls and more standardized assays.


One possible reason I can think of is that the immune system in the brain is somewhat different from the rest of the body; not quite on par with say the mammary glands, testes, or eyes. Obviously I am not a doctor etc, anti biotics etc can have reduced effect in body parts that have reduced or modified immune responses; maybe anti fungals are similar?


It is true that medication penetration of the blood-brain barrier and delivery to the brain is different from other organs (each organ has unique characteristics in this regard).

But we do treat people with CNS infections routinely, including CNS fungal infections.


Good question. Are anti fungal molecules small enough to cross the blood brain barrier easily?


Yes, a bunch of them, including fluconazole, which is a first-line treatment for common fungal infections.


There was recent speculation that alzheimer's was transmissible (prion thing). The transmissibility would make sense if it were actually the fungi causing the build up of the proteins and other damage.


From what I recall, the results in a study showed that the primary care giver of an alzheimer's patient was more likely to get alzheimer's themselves. The argument against transmissibility was that primary care givers tend to be related to the patient.. therefore the more likely reason for caregiver alzheimer's is genetics.


Or as primary care giver they are exposed to the same environmental factors the sufferer is exposed to, but are generaly younger so more resistant until later life.


This article does NOT provide compelling evidence that fungi are the causative agent for AD. It merely reports correlative observations.

You may conclude that antifungal drugs could help patients with AD. You may also think that vaccination or some other mechanism of prevention could reduce the prevalence of AD. These conclusions are simply not supported by the data.

I am a biomedical data scientist, not a neuroimmunologist, so I asked a colleague in my MD/PhD program who has experience in the latter field. His thoughts:

"There are a number of concerning issues here:

1) They are using polyclonal antibodies. I don't think they addressed possibility of cross-reactivity. Comparing Alzheimer's disease vs control brain is like comparing apples and oranges. There can be very different inflammatory states between the two and yield different antigenic environments.

2) The possibility that neurofibrillary tangles or amyloid plaques are sticky and can non-specifically bind antibodies remains a possibility.

3) Only immunohistochemistry? Could have at least done some qPCR especially since they can grow these fungi for quantiation. The only other paper that observed fungus in CNS of AD patients is by the same group. The high possibility of artifact is has not been ruled out."

*edited grammatical typo


Interesting. Does this mean that a treatment with fungicides may stop/prevent AD onset or progress?


Depends on which way the arrow of causality points. If AD makes the brain vulnerable to fungal infection, probably not. But if fungal infection causes AD, then it seems likely.

This might be a giant breakthrough, or it might be just a side effect. The uncertainty is not fun at all. But if the arrow points the right way, then yes it's possible that antifungals would be a big part of treatment.


In either case it makes a lot of sense to start dosing patients with anti-fungal medication and see if their symptoms improve. Usually you do not give fungicide to patients because it has a lot of side-effects but those drugs are readily available and easily prescribed.


It's worth a try, especially if they're pretty far advanced.

Doctors have the whole "first do no harm" thing that makes prescribing stuff randomly on hope not really an option. Now if patients start clamoring for it that's another story. But until it's shown that antifungal medicine does more good than harm (who knows, maybe killing all the fungus somehow leaves a void that bacteria could come fill) it's probably best not to do so widely.


Not sure why you got downvoted. It would have to be done in double blind trials vs placebo, but it would be a great way to test the causal link between fungi and symptoms. You'd have to make sure the fungicides cross the blood brain barrier in patients.


Haven't we studied the effects of Alzheimers enough not to need the control group? I worked in clinical trials and one study still haunts me knowing what happened to the control group.


Sure, it fits right in with the plan to get rid of those pesky controls when testing painkillers too: "Drug companies have a problem: they are finding it ever harder to get painkillers through clinical trials. But this isn't necessarily because the drugs are getting worse. An extensive analysis of trial data1 has found that responses to sham treatments have become stronger over time, making it harder to prove a drug’s advantage over placebo. [...] For companies trying to develop treatments, one remedy might be to compare new drugs against their best competitors instead of against placebo — or to go back to conducting smaller, shorter trials." http://www.nature.com/news/strong-placebo-response-thwarts-p...


Comparing old vs new is how it's done in cancer research. It's inhumane to prescribe placebo to someone in serious pain. You give them the old or the new, and they report how they felt.

In this case, since there is no concept of old or new, it's an entirely new class of treatment. So you give the current best-practice treatment without anti-fungal, and you give the same with anti-fungal.

Anyone in the study is agreeing at the onset that they have a 50/50 chance they will either get the current best practice, or the exact same thing but also the anti-fungal. These are volunteers who are helping move the anti-fungal research forward for everyone, in exchange for a chance of getting early access. They can also leave the study at any time after starting, but if they are in the anti-fungal group they would lose access to it if they did.

If that's not enough, there are cases (e.g. in cancer research) of de-blinding the study when there's a clear/strong positive effect and providing early access to all enrolled if it becomes obvious the new treatment is widely beneficial.

So I think we have the theory behind the ethics fairly well wrapped on how to roll out these drugs. I don't think in practice it works so well, the studies are often poorly run and poorly administered making them extremely more costly than they should be.


The place where I worked did a pretty good job at administering the studies. The cost was in all the sampling and shipping. When your study is doing 1,000 sample kits with 5 samples every week day for multiple years, its going to cost.

I am still a bit clueless with all the research we have done with Alzheimer's why we need another control group?


The control group, with double blinds, provides evidence that the change in treatment causes the change in outcome. If you test without a control, the change in outcome could be a result of any other changes between the test protocol and previous control groups.

You might be able to do a small study without a control to test feasibility of the hypothesis, but I don't know if that would pass ethics review; would probably depend on the side effects of the anti-fungal. Another less invasive way would be to test for fungal presence in groups with and without the disease, likely through autopsies, since sampling a live brain seems intrusive.


Here's my problem, we know the outcome of Alzheimer's, surly we have the data to go ahead without a control group? We've had them before.


Without the control group, you don't know if the change you think you made is the change that made a difference.


I think it really comes down to the strength of the effect. If the anti-fungal has only a marginal effect on outcome, a large n control group helps tease out statistical significance. If the anti-fungal has a strong readily observable effect, the whole study gets un-blinded and everyone starts getting it pretty quickly anyway.

The reality is the control group and the test group are not the exact same people and often it's not even completely true everyone is dealing with the "exact same" disease (different genes, different mutations, different past treatment regimens, etc.). I definitely believe there are cases where a control is setup because "that's how it must be done" and not because it's going to actually provide any useful data at the end of the day to tell you anything about how the test group actually performed.

Another way I've seen this done which is a little less wasteful, and when you have high confidence in your new treatment, is to tweak the standard treatment marginally in some way you think might provide some small improvement in both groups, but in a way that could never justify its own full study. Like you modify the dosing schedule, add some vitimin, diet, or exercise change in some way you think will help both groups. But again you can only afford to do that if you are expecting a very strong effect from your new additive treatment which would blow away your tweak statistically, else you risk hiding a small benefit of the new treatment in your tweak.

In other words, you give every participant the best damn chance and the best care you can legally give them, and 50% of them know they are on something new which could be a blockbuster, and if it is, the whole group will get early access to it anyway.


Ok, but don't we have a body of knowledge on Alzheimer's that having another control group is redundant? Why do we keep needing new control groups for things that are going to kill people and we know are going to kill people? I cannot get by the ethical problem of knowing we're kill 50% of the people in the study to provide data we already have.


The problem is, if something related to how you run your test of the anti-fungal has an effect on the disease, you're going to assume its the anti-fungal; but maybe it's not. If you have a control group, and both groups do better than expected (compared to the body of evidence), then you've learned something you wouldn't have without a control group (and you'll have to work hard to figure out what changed in this study vs other studies). If anti-fungals are a clear winner, it's likely that the study protocol would be changed to give everyone the drug after early results.


The control is either "no treatment" or "treatment as usual".

Those have problems of blinding, and treatment vs no treatment is difficult to get through ethics committees.


Is that 1,000 patients enrolled each being tested daily? That is a heck of a lot of testing!

Obviously depends on the patient population (in/out patient) but IMO a huge component of the cost is pushed off on patients having to spend a day getting to the study facility to give blood and urine versus dropping it at a local lab.

Then again, if Theranos tells us anything about variability of lab results, you certainly have to take every precaution to protect the integrity of your data.


My sarcasm detector is busted, are you for or against control group in this situation?


Perhaps you are basing this on the incorrect premise that Alzheimer's is understood at all. It isn't, and worse essentially no progress has been understanding it for many years. For example, the purpose of APP (amyloid precursor protein) remains mysterious. The same speculations are thrown around now as by the guy who discovered it in the 1980s.

At some point you need to start considering that something is seriously wrong with the research methods or theories. This fungal idea is good to explore, but the evidence provided here is not convincing at all.


Given that there is a low incidence of AD in India, i'd suspect that fungal infection is partly a cause. It would be interesting to plot food spiceyness vs AD rates and spiceyness vs fungal infection rates in the world population.


There was some promising research on using turmeric, the stuff that gives curry it's yellow colour, to treat Alzheimer's:

>We describe here three patients with the Alzheimer's Disease (AD) whose behavioral symptoms were improved remarkably as a result of the turmeric treatment...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665200/

Turmeric has strong anti fungal properties.


The paper mentions in passing in the discussion section:

"Moreover, antifungal treatment in two patients diagnosed with AD reversed clinical symptoms [51,52]. The interpretation of these results was that perhaps these patients were misdiagnosed."

[51] Ala, T. A., Doss, R. C. & Sullivan, C. J. Reversible dementia: a case of cryptococcal meningitis masquerading as Alzheimer’s disease. J Alzheimers Dis 6, 503–508 (2004).

[52] Hoffmann, M., Muniz, J., Carroll, E. & De Villasante, J. Cryptococcal meningitis misdiagnosed as Alzheimer’s disease: complete neurological and cognitive recovery with treatment. J Alzheimers Dis 16, 517–520 (2009).


Wow. So there's a possibility that they were, in fact, diagnosed properly with Alzheimer's, and accidentally treated properly. Amazing.


I know that toenail and fingernail fungus infections are very common (see, e.g., tons of late-night TV ads). Any chance that those kinds of infection could make their way into the brain?


The article mentions infection of blood vessels so it seems likely that the fungi make their way into the brain from other sites.

Perhaps the fungi avoid the immune system by being very slow and relatively non-disruptive, and the reduced effectiveness of the immune system in old age allows it to take hold and spread.


I wrote a comment in another subthread but basically that's not likely to happen anytime soon due to two factors. 1) currently available antifungals (for internal fungal infections) are not nearly as powerful and quick as we think of "regular" antibiotics to be even in the organs that get plenty of medicated-blood supply and 2) Blood-brain barrier means that it's hard to deliver any medications to the brain tissue (https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier#Fu...)


This seems like potentially an incredibly important breakthrough with a perplexingly weird title. Different brain regions? Different to what? From reading the study, the novelty is not about the "difference" of the brain regions, but the fact that fungal infection is found in AD patients at all. The controls had no infection, not different infections in their brains.

I'm curious if the title makes sense to people in the field or is this weird to them too?


As a layman, i understood the title correctly I guess. That there were fungi not just on one spot, but different (ie several) regions.


But that would be bad English. I wouldn't expect the Nature editors to let such bad English slip through in an important title, but I admit it is frustratingly common to see people not caring too much about that sort of thing.

I had the same concern as GP. I don't understand the title; the controls seem not to have fungi in their brain, which had always been my assumption about, for example, my brain.


After reflecting I am wondering if this is a result of the natural tendency of scientists to avoid any hint of overstating their work. Were the fungal infections all in the same region or by the same fungus it'd be absolutely shocking. It'd be a "cold fusion" level revolution for the field - and a "cold fusion" level embarrassment for them if they are wrong. So they are extremely keen to put up front that the picture is not nearly so clear as that.

There is also a tendency when scientists are extremely confident they have found something incredibly important to understate it. I always think of the Watson and Crick "It has not escaped our notice ..." statement in this context.

This is all based on guesswork though, so that's why I'm curious about what people in the field think.


So, interpreting "different" as "multiple"? Seems unnecessary to use an ambiguous word. And then an ambiguous word that is not actually the main point of the study.


They meant multiple, the authors are from Spain. I'm not sure why an editor wouldn't try to alter the title though, perhaps they are also not native english speakers.


I just moved out of a place I'd lived for 5 years that turned out to have black mold. I've had weird digestive issues and my immune system has gone to shit since living there but I wasn't aware of the mold problem and didn't know of the health problems it could cause. So this study is pretty terrifying; I should probably get tested.


Is there any relation to the study that suggested AD is diabetes type 3? Insulin resistance + fungi?


Candida is a common opportunistic infection in diabetes type 2, so there's a few ways in which correlations could be observed. The fungal infection could be a symptom of the underlying "type 3" diabetetes; or the CNS fungal infections could be more common in diabetic or pre-diabetic people, leading to AD.


If you've ever taken antibiotics for an extended period and ended up with a fungal infection due to the loss commensal bacteria this is pretty intriguing. There is a lot of new literature proposing links between gut disruption and neurodegenerative disease.


Maybe antibiotics cause Alzheimer's.


For what it's worth, the institution [1] behind this study is one of the most prestigious scientific institutions here in Spain.

[1] http://www.cbm.uam.es/


Are there other internal diseases caused by fungus? Obviously there are fungal skin infections, but it sounds strange that a fungus would be able to live inside the body.


This is extraordinary. It means antifungal drugs like Fluconazole can possibly prevent AD.


No, it means that a researcher doing fourth rate science has successfully trolled HN.


Please stop posting unsubstantive comments to Hacker News.


Nature is not a good scientific journal. The good info will be found in highly specialized journals. The amount of BS in scientific journals is related to prestige like this:

x=seq(0,1,by=.01);

plot(x,dbeta(x,.5,.5), xlab="Prestige", ylab="BS")


We detached this subthread from https://news.ycombinator.com/item?id=10403159 and marked it off-topic.


For those without a R interpreter handy, Emacs to the rescue:

       ^
       |  |                                                                           |  
       |  |                                                                           |  
       |  |                                                                           |  
       |  |                                                                           |  
       |  \                                                                           /  
       |   |                                                                         |   
       |   \                                                                         /   
       |    |                                                                       |    
       |    \                                                                       /    
       |     \                                                                     /     
       |      \                                                                   /      
    B  |       \                                                                 /       
    S  |        \                                                               /        
       |         -\                                                           /-         
       |           \                                                         /           
       |            -\                                                     /-            
       |              -\                                                 /-              
       |                --\                                           /--                
       |                   --\                                     /--                   
       |                      ---\                             /---                      
       |                          -----\                 /-----                          
       |                                -----------------                                
       |                                                                                 
       +--------------------------------------------------------------------------------->
                                            Prestige
(Also an on-line R interpreter: http://www.r-fiddle.org/.)


What package(s) did you use to create this?


I used http://r-fiddle.org to verify what was the intended function, then used built-in Artist Mode (M-x artist-mode) to draw an ellipse for function and square for axes, and finally cut it down in fundamental-mode and added labels. It's basically vanilla Emacs, but I admit to using multiple-cursors.el for some cleanup. It's an excellent addon mode offering a more interactive way to do some things you'd otherwise do via keyboard macros. Check out [0] and [1].

[0] - https://github.com/magnars/multiple-cursors.el

[1] - http://emacsrocks.com/e13.html


Ah thanks, I was aware of artist-mode, I thought there was some ESS like package that could output ascii graphs of functions :) R-fiddle is new to me though, thanks for that.


There's also orgtbl-ascii-plot[0], there was a mode for writing out flow diagrams in Emacs that used a web backend to render them (I don't remember the name), and I'm pretty sure you could abuse some graphics-to-ascii or DOT file command line tools to get the required result in Emacs buffer - particularly via org-babel, which lets you invoke external programs to "evaluate" code blocks. I remember using some Java-based local tool to render graphs through org-babel, but again I don't recall the name or URL.

[0] - http://orgmode.org/worg/org-contrib/orgtbl-ascii-plot.html


Sounds like Bozo the Clown is now publishing articles in Nature.

One problem with biomedical research is the crackpots.


Are these fungi from Yuggoth?




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