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A Fungal Origin For Alzheimer’s?

Here’s a potentially interesting paper that’s recently appeared, saying that numerous brain regions in Alzheimer’s patients appear to show signs of fungal infection, as opposed to control samples. The authors claim detection through antibodies, and to have isolated fungal DNA as well, identifying several species.

The authors (from two groups in Madrid) have advanced this hypothesis before, and this paper seems to be an attempt to provide more evidence. I’m not enough of a histopathologist to say how strong that evidence is. The microscopic structures they identify as fungal cells do seem to stain fairly distinctly with antibodies, but (1) I don’t know the microanatomy of human neurons enough to say that that’s what these structures are, and (2) the antibodies themselves are polyclonal, and can potentially cross-react with other targets. (The authors, though, say that the observe no cross-reactivity with human proteins, only with other fungal species). They see evidence of fungal structures in both the neurons and in the cerebrovasculature as well.

Most of the figures in the paper are from one Alzheimer’s patient and one control, but the study did look at an additional ten patients in each category. The authors say that the same pattern repeated, with signs of fungal infection in all the AD samples and none of the controls. The structures seen in the histopathology slides vary, which could be completely believable, or could also be a versatile form of wishful thinking. And as mentioned, they were able to PCR out fungal DNA from these tissue samples, with different patients showing different mixtures of species present (and no one sample ever showing just one species). This is described as a nested PCR assay, which had to be set up carefully to detect very small amounts of fungal DNA, and again, I can go both ways on this: this sort of painstaking work may be exactly what’s needed to amplify such samples, or it could be a form of turning up the gain so high that you start reading out patterns in the noise.

There’s also a cause-and-effect question: if fungal infection does turn out to be associated with Alzheimer’s, does it mean that such infections give you Alzheimer’s, or that Alzheimer’s makes you more prone to the infections? This is a question that can be answered in the clinic, and I think it should be. There are a lot of antifungal drugs to choose from, and there are certainly a lot of Alzheimer’s patients out there. The authors reference two recent cases in the literature of cryptococcal meningitis “masquerading as Alzheimer’s disease”, and suggest that the improvement seen in these patients on treatment with antifungals might be a more widespread phenomenon. That would be quite a breakthrough, but I also wonder how many other people with AD have had systemic antifungal treatment over the years, presumably without such clinical outcomes. (On the other hand, the most common therapy for cryptococcal meningitis is amphotericin B, i.v., which is not something that you do lightly, so there may not be as many overlapping cases as you’d think(.

At any rate, this hypothesis goes into the “well worth testing” category, because the barriers to such testing aren’t high, and the potential returns are so great. It’s a long shot, but the bacterial origin of ulcers was a long shot, too, and that one was completely correct. I hope someone takes the authors up on it!

22 comments on “A Fungal Origin For Alzheimer’s?”

  1. anon says:

    You are posting comments too quickly. Slow down.

  2. Oliver H says:

    Fungal infections of the brain aren’t really a new concept and the question would be why we don’t see the typical immune responses, meningitis, abscesses etc. Also, wouldn’t we expect Alzheimer’s to be more common in immunocompromised patients? Especially if we don’t see the typical signs of inflammation?

  3. Mo Shoreibah says:

    The paper is very intriguing however one has to prove causation and not just correlation. Immunohistochemistry with polyclonal antibodies is hardly sufficient evidence to support the claims made by the authors. The antibodies could be recognizing a glycan epitope common to both fungi and humans. The PCR data is harder to dismiss. If there is any follow-up to this research it ought to be an animal model that can replicate the findings of this paper. In addition, animals successfully infected with these pathogens should be treated with systemic antifungals to reverse any neurological deficits observed in the infected animals.

  4. johnnyboy says:

    Speaking as a pathologist, this is complete rubbish. Showing only confocal images, seriously ? How about some standard histologic sections, with normal tissue and fungal stains, which would be entirely sufficient to show fungal organisms of the size they are describing (1-10 um) ? No you don’t want to do that, because it would be apparent that there is nothing there – much better to use techniques prone to lots of false positive reactions, like IHC and PCR. Also, make sure that you do your fluorescent IHC on paraffin-embedded tissue sections, so that you get loads of background tissue autofluorescence – this way you make sure you’ll have some sort of “positive” signal. Oh and don’t bother with even trying to explain why fungal infections, which normally cause massive inflammatory reactions and tissue necrosis, in this case would just sit there quietly for years in the walls of vessels. What a load of mierda.

  5. anona says:

    ” Also, wouldn’t we expect Alzheimer’s to be more common in immunocompromised patients?”

    As you age you immune system begins to fail. This would seem to correlate pretty well with the onset of Alzheimer’s due to a fungal infection.

    1. Oliver H says:

      “As you age you immune system begins to fail. This would seem to correlate pretty well with the onset of Alzheimer’s due to a fungal infection.”

      Not really. Because there are plenty of HIV and cancer patients whose immune system is far, far worse than that of an ordinary elderly person. These are also the usual suspects for a fungal infection of the brain.

  6. Lane Simonian says:

    The key pathway once again here is phospholipase C, protein kinase C, NMDA receptor activation, p38 MAPK, peroxynitrite.

    We conclude that Plc1 is a central regulator of cryptococcal virulence, acting through the protein kinase C/MAPK pathway, that it regulates release of Plb1 from the plasma membrane and is a candidate antifungal drug target.

    http://www.ncbi.nlm.nih.gov/pubmed/18532984/

    The number of activators of phospholipase C is quite numerous and that explains why the causes of Alzheimer’s disease are numerous and why the disease affects so many people.

    The other pathway activated by phospholipase C involves the release of intracellular calcium. Via calpain this leads to amyloid oligomers and plaques and hyperphosphorylated tau. A number of compounds inhibit this pathway so it is possible to have Alzheimer’s disease with little or no amyloid plaques (some researchers call this primary age-related taupathy, but it is really Alzheimer’s disease without amyloid plaques). And until the brain’s antioxidant system is depleted it is possible to have plenty of amyloid oligomers and plaques and hyperphosphorylated tau without having Alzheimer’s disease.

    The likely cause of Alzheimer’s disease is oxidative stress (and again there are dozens of causes for this stress). The likely treatment for Alzheimer’s disease are powerful antioxidants.

  7. Anon says:

    I think the most likely cause of Alzheimer’s/dementia is reading endless comments on peroxynitrites… seriously, it’s doing my head in, I need to get out of here.

  8. Dave says:

    The next question would be whether the fungal infections are contagious, either via airborne pathways, or via blood transfusions?

    Dave

  9. luysii says:

    It’s deja vu all over again (apologies Yogi). There was a huge literature showing that multiple sclerosis was due to a variety of infections (coronaviruses etc. etc.). None of it panned out.

    However, since we have no useful therapy for Alzheimer’s disease, weird ideas about causation are to be welcomed, since they might lead to a therapy, however far fetched. Here are two more examples — https://luysii.wordpress.com/2014/11/30/could-alzheimers-disease-be-a-problem-in-physics-rather-than-chemistry/

  10. anonymous says:

    There is equally as much evidence for herpes simplex. This is only really going to be solved in the clinic as you can pretty much find whatever causation agent you like in the literature, which in itself tells you something. Hell, Lane Simonian may even be right, but these theories really need to be tested in people.

  11. tally ho says:

    fungal contamination of tissue samples perhaps? spores, spores, spores…

  12. Jose says:

    Hey johnny-boy, you should most certainly post your comments on pubpeer:

    https://pubpeer.com/publications/26468932

  13. steve says:

    We seem to have forgotten Koch’s postulates. If Alzheimer’s is due to fungal contamination and they can isolate the fungi then the next step is to stick them in some primates and see if they develop the disease.

  14. johnnyboy says:

    Thanks Jose, I will look into it.

  15. a says:

    From another website:

    Oh man, the list of fungi they identified in the brains is like an itemized list of common fungi that contaminate DNA reactions in the laboratory.

    and

    I cannot stress this enough; if you are ever working on a fungal sequencing project, and the result is ‘Malassezzia, Candida, and Saccharomyces’, the proper response is not ‘publish a paper’, it’s ‘dump your reagents and bleach the lab’. Oh, and I missed this before, but Neosartorya is just the sexual state of Aspergillus. The only box on the common laboratory contaminant checklist they are still missing is Pichia.

    The collection of fungi listed is also biologically implausible. There are ascomycetes and basidiomycetes, some of which are primarily yeast-like, and others which are mold-like. Some are animal-associated, some are environmental saprobes, some are common plant pathogens. There is basically nothing holding them together as a group except that they’re all members of common genera.

  16. Gaear Grimsrud says:

    Where is mitochondrias house? (the ultimate invasive pathogen)

  17. Lane Simonian says:

    In regards to the connection between viruses (including Herpes simplex) and oxidative damage:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2327086/

    The singular explanations for Alzheimer’s disease may be correct in the sense that by themselves, they may be sufficient to trigger the disease but they are incorrect in suggesting that they are the only cause of the disease. In regards to certain bacterial, viral, and fungal infections, it has not been determined whether they alone can trigger Alzheimer’s disease or whether other risk factors (high glucose levels, high sodium levels, stress, exposure to environmental toxins, certain genes, etc.) must also be present to initiate Alzheimer’s.

    No matter what the initial trigger, the final result is always the same: cysteine oxidation, tyrosine nitration, lipid peroxidation, DNA damage, mitochondrial dysfunction, and apoptosis. If the treatment only addresses a particular cause (an anti-fungal treatment, for instance), it may help some people but not many. If the treatment addresses a particular cause (bacterial infection, for instance), but has broader application (acting as an antioxidant) then that type of treatment can potentially help anyone with Alzheimer’s disease.

  18. Sounds like that old “cancer is really a fungus” quackery,

    Somebody get Tullio Simoncini on the case, maybe he can write “AD is a Fungus” and pitch baking soda as the cure….just like he does with cancer.

  19. Lane Simonian says:

    This is a simply brilliant quote:

    Dr Carrasco and his team think a clinical trial of anti-fungal drugs is the next logical step. But there is yet another possibility. In the absence of a definitive ultimate cause, it may be that the symptoms of Alzheimer’s disease can arise from many different types of insult to the brain. There have been several papers, says Dr Le Guillou, that have found correlations between various infectious organisms and Alzheimer’s. “It could be a bit like the Mississippi river,” says Dr Hardy. “You can start in all sorts of places, but eventually you’re going to end up in New Orleans.” If Alzheimer’s is a general response to all sorts of neurological triggers then it may be that the fungal infections found by Dr Carrasco are simply one of a long list of causes.

    http://www.economist.com/news/science-and-technology/21676754-curious-result-hints-possibility-dementia-caused-fungal

  20. Benjamín Wizel says:

    A fungal infection might be just one trigger factor amongst many and it might still require some level of host susceptibility (eg. genetic, immune) to AD. It is worth to further pursue studies that should aim at reproducing and extending the data shown in this study and at validating results with other methods. A clinical study to assess the effect of antifungals in cognitive decline should be relatively easy to implement.

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