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Alzheimer's Disease

Alzheimer’s and Infectious Disease: For Real

I’ve written a couple of times over the years about the idea that Alzheimer’s disease might have an infectious component to it. That’s been proposed many times, but it’s fair to say that it’s never caught on. For one thing, the amyloid hypothesis has always had a lot more going for it. I realize that I’ve poured scorn on that one in recent years, but that’s after a string of massive clinical failures based on it being right. It started out as by far the most plausible mechanism around, and even now, any further explanation of the disease is going to have to include an amyloid component, in much the same way that Einstein’s relativity also included an explanation of why Newtonian mechanics was so workable so much of the time.

A new paper in Neuron, though, looks to be the most unignorable one yet with evidence that there’s some sort of viral/bacteial/fungal component to the disease. A team led out of a Mt. Sinai research group has gone over a pretty large sample of Alzheimer’s brain tissue (622 patients who died with the disease, and over three hundred control brains as well), sequencing infectious organism DNA, looking for changes in the proteome, etc. They find that aging brains in normal patients display plenty of viral signatures (as indeed is probably the case in many other tissues). But the AD samples were particularly enriched in herpesviruses 6A and 7, a result that repeated across three independent cohorts from different geographical locations (the brain tissue collections were from more than one previous effort). According to Stat, there’s a paper coming out next month from another group entirely that also implicates HHV6.

But are these viruses a cause of the disease, or are they something that shows up later? That is, do HHV 6A/7 give you Alzheimer’s, or does having Alzheimer’s bring on those viral infections? This has been the problem with many previous proposals for an infectious agent, and it’s a very difficult objection to overcome. I think that this is the first study, though, that has made it over that hurdle. The paper shows that viral DNA is, in fact, incorporated into neurons from the affected regions of the brain. What’s more, analysis of both protein and mRNA levels suggest that such infection produces changes in several transcriptional regulators (specifically, a set of zinc-finger transcription factors and G-quadraplex-associated proteins) that in turn affect expression of a number of very suggestive proteins downstream:

We found that multiple viruses interact with AD risk genes. HHV-6A stood out as notable with significant overlap (FDR < 3e-3) between the set of host genes it collectively induces across all tissues and AD-associated genes (Figure 5D, Table S7). This includes several regulators of APP processing and AD risk-associated genes, including gamma-secretase subunit presenilin-1 (PSEN1), BACE1, amyloid beta precursor protein binding family B member 2 (APBB2), Clusterin (CLU), Bridging Integrator 1 (BIN1), and Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM). We also found that several other viruses regulate, or are regulated by, AD risk genes, including: (1) HAdV-C-induced expression of Complement Receptor 1 (CR1), and inhibition of Solute Carrier Family 24 Member 4 (SLC24A4), (2) inhibition of KSHV by Fermitin Family Member 2 (FERMT2), and (3) inhibition of HSV-2 by Translocase of Outer Mitochondrial Membrane 40 (TOMM40). These findings indicate multiple points of overlap between virus-host interactions and AD risk genes.

There’s also an association with neuronal loss, and this and other pathways seem to converge on miR-155 as an important factor (HHV6A inhibits its expression). The team then crossed a mouse strain that’s knocked out for this microRNA with one of the APP/presenilin mutant mouse lines that is susceptible to amyloid problems. And indeed, the resulting mice  show significantly more amyloid plague formation at four months, and significantly more amyloid 1-42 in the brain.

This gets right at what I mentioned above: any alternate theory of Alzheimer’s will have to explain why there are so many apparent connections to amyloid handling. So this might well be real, and if it is, it really does open up a whole new set of mechanistic (and even therapeutic) possibilities. Although I don’t keep up with the literature in this field as well as I would were I still working in it, I think that this is one of the most significant Alzheimer’s papers I’ve seen in years. A mechanism through viral disturbance of transcription factors, miRNAs, and other such gene-expression pathways would fit well with the variations seen in the incidence and severity of the disease, because that lands you right into the mess of environmental factors, immune system variations, and so on.

The integrated findings of this study suggest that AD biology is impacted by a complex constellation of viral and host factors acting across different timescales and physiological systems (Figure 8B). This includes host mucosal defense and modulation of innate immune response by virus and host. It also includes disturbance of core biological processes, including some that are well described in AD (e.g., APP processing, cytoskeletal organization, mitochondrial respiration, protein synthesis, and cell-cycle control) and some that are less well characterized (e.g., widespread shifts in G4 activity and C2H2-TF regulatory programs). We note potential mechanisms (and candidate molecular mediators) that we find perturbed by viral species and that have known impacts on these altered processes, for instance, virally driven changes in protein synthesis machinery, tRNA synthetase activity, and nucleotide pool maintenance, which collectively exert complex effects on G4 regulation and C2H2-TF activity.

This paper immediately suggests several lines of research. HHV6A needs to be studied in more detail (and distinguished from HHV6B, which current tests don’t always do). Viral mechanisms of transcriptional disruption have already been investigated in other contexts, but there’s a lot to be done in the Alzheimer’s territory. We need to see if miR-155 is a real node in the system, and so on. And it wouldn’t do any harm to look at the effects of existing antiviral drugs on these HHV strains, would it? After years of writing about amyloid-centric disappointments, I think it’s great to have some new hypotheses to test!

58 comments on “Alzheimer’s and Infectious Disease: For Real”

  1. Eric says:

    Very interesting work. One thing that was difficult for me to determine from the correlation data they published – what % of the AD patients displayed increased viral load? In other words, are there patients that don’t have any evidence of a viral component or is it nearly universal?

    1. MTK says:

      That’s a good question.

      There’s certainly a school of thought that AD is many different diseases from a molecular standpoint that all result in a common phenotype.

  2. kjk says:

    This is amazing. If correct, now we at least have a lever that can be puled: antiviral drugs to the brain. All of the sudden treating what is by far the worst way to die went from impossible to very difficult, which is a HUGE step.

    1. Ian Malone says:

      Antisense therapies for Huntington’s Disease are beginning to show promise and people are starting to try it in AD. These are delivered intrathecally, so if it turns out antivirals are the answer instead…

  3. anonymous says:

    I am not an expert but curious if as a result of HHV6 the inflamed neuron cells trigger production of peroxy nitrates that causes more runaway damages etc., a theory very strongly proposed by Mr. Simonian in these site?

    1. t says:

      As a carpenter with a hammer, I wonder if this HHV6 infection triggers the production of nails.

    2. Me says:

      Awww man! you beat me to it!

    3. MoMo says:

      Absolutely, and the treatment of Lane on this blog will cause all you naysayers and Simonian slaughterers nightmares someday.

      1. Dolph Dümpling says:

        Emmm, f****** NO, “Lane”! Absolutely not!
        You and your “oxidative stress”-BS are actually finally proven wrong with this paper. But I guess your CNS viral load is so high you simply aren’t able to realize this

    4. Matthew K says:

      Good thought, “anonymous”, why don’t we just redirect the discussion of viruses to peroxynitrites?
      For the record – I am happy for Lane to hold his views, and I reckon it’s possible that such a mechanism is significant in AD, I just objected to his relentless hijacking of every single discussion about any possible aspect of AD to restate exactly the same litany of ideas and oblique evidence. It’s the behaviour of a boor or a crank, or a little of each.

      1. MoMo says:

        Back at you on the litany of regurgitated theories. But this is a blog and anything goes on the Internet Wild West. He probably got under everyone’s skin because he pointed out shallow theories that have been beat to death yet still are in vogue. But lets see how the “New” kids on the block like Denali and others fair with the pathway to success in AD littered with corpses.

        Target based monotherapy for complex neuro diseases hasn’t worked yet, so why start now?

        1. Vader says:

          “But this is a blog and anything goes on the Internet Wild West.”

          This isn’t the Wild West. This is Derek’s living room. And when a drunk wanders in off the street, pisses in his potted plants, and propositions his wife, the appropriate response is to usher the drunk back out to the street.

  4. Me says:

    Like the work – I always had time for the other major theories on AD, but focussed mainly on metabolic, mitochondrial, proteostasis, lysosomal storage……..

    A long way to go with any of these but nice if the dialogue has changed.

  5. Anonymous says:

    I haven’t read the Neuron paper, just Derek’s summary. Many an organicker knows to consider the possibility of contamination of samples during processing (grease peaks in an NMR; rearrangement or modification of natural products into non-natural products during isolation; decomposition in the fridge; etc.). Cell biologists have their histories of cross-contaminating cultures (human cells overtaken by stray monkey cells; HeLa cells can take over almost any cell culture; the Gallo HIV virus that was actually the Montagnier LAV virus, due to contamination; etc.). I’ve had friends describe the occasional need to completely shut down and fumigate cell culture facilities.

    Procedures are probably much better today, but I am still having to ask those in the field: How common is it to see contamination in labs processing cells and viruses? What is the possibility that the virus in the samples was post-processing contamination?

    1. Anonymous says:

      Commenting on my own comment: I guess there is WAY too much happening in the neurons to occur from post mortem contamination. But I had to ask.

    2. HFM says:

      Honestly, contamination was my first thought. I wonder if this would replicate if you tested for Alzheimer’s risk in seropositive vs seronegative patients, not just testing some brains that have been shuffled around in the freezer forever.

  6. Brian says:

    Do current antiviral drugs (like acyclovir) penetrate the CNS? If so, is it possible to see if people in their 60’s and 70’s who have been treated for shingles with acyclovir or other antivirals have a reduced incidence of Alzheimer’s?

  7. loupgarous says:

    What if, like JC virus, HHV6/HHV6b are things that exist at low levels in a large part of the human population but don’t cause AD unless the immune system is weakened in a certain fashion?

    There’s a list of biologics (rituximab, natalizumab, efalizumab) associated with progressive multifocal leukoencephalopathy when (presumably) a prior, low-level JC virus infection was re-activated, and other drugs such as Tecfidera are implicated in PML in the same way.

    The herpesviruses seem to activate at a lower threshold of immunosuppression than JC virus (to me, anyway). It’s worth a think.

  8. JeffC says:

    I saw this too and thought it was really interesting and really well done. I spent some time some years ago talking to Ruth Itzaki at Manchester and she had her data around HSV and it’s apparent link to Alzheimer’s. The thing that was clear was that while the amyloid crowd thought she was some kind of fringe nutter, she was entirely rationale and had made a scientific observation that was interesting and merited some investigation. I had fairly low expectations but she really was excellent. While this paper focuses on HHV, I think there is a broader herpes virus link; HSV is still showing up as doing something.
    To the question of whether these viruses are causative (and this paper does a great job of getting to that) I think the evidence is mounting that they are. Viruses are quite simple. They exist to replicate and pretty much nothing else. In some cases the effect is short term (flu, rhinoviris etc) and in other cases the effects are seen many years later, eg HCV. These patients are right at the end and so we don’t know if this is about acute infection or something else. I rather suspect that there is some type of ongoing viral load (which will have a genetic component that makes some patients more susceptible to rapid progression or disease) that eventually causes a problem. It stands to reason, these viruses shouldn’t be there and it shouldn’t be a surprise that if left untreated that eventually they cause a problem.
    So, could it be as simple (simple conceptually as opposed to finding a treatment) as treating an infection? If we prevent replication or eliminate the virus will that work? Do we need a pan-herpes virus inhibitor?

  9. a. nonymaus says:

    So, is it possible to develop a vaccine that would prevent HHV6/7 infection before the virus establishes latency? As a DNA virus, it should be genetically stable enough to target.

  10. bacillus says:

    According to this epidemiological study people with HSV infections taking anti-herpetic medicines for as little as 28 days can reduce their subsequent risk of developing dementias in general by up to 2.5-fold. As someone who has suffered from cold sores his whole life, I’ll be talking to my family Dr. about a month long course of acyclovir very shortly. Can’t do any harm, though we don’t have right to try legislation here in Canada

    1. JIA says:

      Thanks for the link to this interesting paper! I have several family members who suffer from cold sores, so I read it with interest.
      But I was disappointed to see that their selected patient population was people over 50 who received a NEW diagnosis of HSV infection. They specifically excluded people who had HSV earlier in life. So it’s not clear whether the results (higher risk of dementia in those with new HSV infection after 50, vs those over 50 who do not get such an infection) will be replicated in individuals with chronic life long infections picked up in childhood or adolescence. A new study would be required to look at this.

    2. Harown says:

      Even better: Antiherpetic medication reduced the risk of developing dementia by a factor of 10.

  11. Uncle Al says:

    Perhaps the disease connection is akin to rheumatic carditis having a streptococcal M5 protein amino acid sequence in part identical to part of cardiac myosin, thus being an autoimmune epitope trigger.

  12. Wavefunction says:

    Laura Manuelidis at Yale has been talking about a viral cause for TSE and Alzheimer’s for years. Not surprisingly, she had a bitter spat with Stanley Prusiner whose prion hypothesis she was challenging.

    1. loupgarous says:

      Manuelidis, and Patricia Merz (scrapie associated fibrils), and Paul Brown (whose paper on kuru and related encephalopathies submitted to NEJM was shot down during peer review by Prusiner, so Prusiner could submit HIS paper which reached identical conclusions, except for the magic word “prion”). If someone did good independent work on the slow encephalopathies prior to the 1990s, odds are good they and Prusiner have had words or worse.

  13. Anonymous says:

    Kudos to the team!
    My Father-in-law had some sort of meningitis infection (probably viral!) some 20 years ago and he was treated for it and the swollen brain that almost impaired him was cured and all was happy until 5 years ago. He picked up one of these deadly CNS disorders ( AD) and is now on death bed (Wish this work had seen the light of the day couple of years ago where we could have tried acyclovir etc and see if he regained his cognizance. Probably, it is not too late to try though he spends most of his day sleeping). So, that is just one other story to support the theory.

  14. ric says:

    Miragen is targeting mir-155 it will be interesting to see if in the future they might target Alzheimers…

    1. MTK says:

      They are, but they’re using a LNA antimir to inhibit mir-155.

      This study correlates low mir-155 levels with increased amyloid plaque formation

      1. Hap says:

        If plaque formation is a problem (cause rather than effect), wouldn’t that be bad, either sooner or later?

  15. David Young, MD says:

    Herpes Virus HH8 was once thought to be the cause of myeloma.
    But no one seems to think that anymore.

    1. Does it matter? says:

      Cancer or AD…it does not matter…they both are bunch of complex diseases ….the nature’s way of shutting down the system…..all of us would just have to postpone getting them as far as possible if we do not die of any other reason…why bother trying to find a cure that only extends the patient’s life by 6 months at best!

  16. An Old Chemist says:

    I have often read in news clips that people with higher education level, and who keep doing mental exercises (crosswords, etc) have a low(er) chances of getting AD. Does any biological hypothesis explain this fact?

    1. Stephen says:

      I think the theory is that being brighter masks the symptoms of AD for longer but the incidence is the same overall.

      1. e.a. foster says:

        That is good to know. Thank you.

      2. e. a. foster says:

        Thank you for the information. It confirms what I thought based on watching people with dementia and some of us looking back once we knew our parents had dementia, either Lewy Body or Alzheimers.

        please keep the match quiz at the bottom very basic, some of us are challenged in that area and need to take off our shoes.

  17. anon says:

    We know even less about virology than we do AD.

    1. Some idiot says:

      I’m not sure I agree about that… I think (a) we agree that viruses are the causative agent for viral infections, (b) (broadly speaking) how they act, (c) (broadly speaking) we have some pretty good ideas as to how to attack them, and (d) we actually have some pretty good drugs for treating some viruses.

      To run the same questions against AD, I would argue that the corresponding answers are something along the lines of (a) there is no real consensus on the causative agent for AD (although this paper may well help a lot in this area), (b) we have some ideas about what AD looks like, but are not really clear about which is the cart, and which is the horse (or horses), (c) we have yet to see a proof of principle for any effective way of treating them (plus, in my view, very significant proof against the principles for certain models), and (d) we have nothing on hand that remotely resembles an effective treatment (and by treatment I mean “something that will make it go away”).

      1. truthortruth says:

        Agreed. Thanks for posting your reply to save others the effort!

  18. Some idiot says:

    I have a question for people who know more biology and virology than I do (i.e. most people…).

    Let’s say that this is the real deal, and that knocking this virus on the head will stop one developing AD (and we have suitable drugs to do precisely this). What are the public health implications for this? As usual, I would guess that one would need to be treated before symptoms appear, since from what I can understand, neuronal regeneration is not really on the cards. What does that mean? Do we screen _everyone_ for the viruses, and treat all who show signs that they may have been infected in order to reduce the risk of them developing AD? Should we treat people prophylactically (my gut feeling screams out “no!”)? How do you screen? Is blood test ok, or do you need CSF? What would the lag time between infection and symptoms look like?

    1. Barry says:

      much more effective than anti-viral therapy has been anti-viral vaccination. But the catch is that a virus that doesn’t provoke much immune response upon infection is a lousy candidate for a vaccine (e.g.small pox was a great candidate, HIV remains a lousy candidate).
      If an efficacious vaccine is possible, universal childhood vaccination (as for smallpox, polio…) might be in order

      1. Some idiot says:

        Yep, good comment… a vaccine would bea really good thing (assuming it works, as you mentioned). Thanks! 🙂

  19. mallam says:

    As per the “cause”, it’s certainly plausible for there to be several confluent or independent influences or causes of AD. Just like other “diseases” that all photogenically appear the same, while actually being of differing origin, and become deferentially categorized only after the causes are identified.

  20. mallam says:

    phenotypically not photogenically, sorry.

    1. milkshake says:

      There was a long-going pathology study done on cloistered nuns (ideal test subjects because of their controlled environment and good medical record-keeping) which correlated the history of their mental decline with postmortem pathology changes in their brains. (“you really have to become friend with them if you are going to ask them for their brains”)

      The conclusion of this study was that some nuns kept their mind sharp almost to their late 90s – and they had lots of plaques and tau hallmarks of AD – whereas others with the same pathology deteriorated in their 70s and developed AD. The AD patients had much higher incidence of micro-strokes and other cardiovascular problems. So it appears that even AD-like afflicted brain can compensate to a great degree unless there is also an underlying cardiovascular issue

      1. Me says:

        ..And I’d add that (long time ago) I’ve seen similar work looking at patients who develop AD and correlating with events of sickness (viral infections being one such event), and that the authors saw correlation between cognitive decline and events of sickness. Could argue that the viral component is the correlating factor.

        Of course, easy to argue ‘it’s all inflammation’, (which is always the argument that anybody who works in inflammation comes out with) and say that the immune system being out of whack is doing the damage.

        Or we could argue that cumulative lifetime viral load of viruses X, Y and Z have some kind of correlation with development of AD symptoms, and all patients will eventually succumb, but AD patients are just the early victims due to increased loads?

  21. Barry says:

    I’d want to know not only the identity of the virus, but where it integrates. It may be that these Herpesvirus like to integrate into a sequence that codes for (or regulates expression of) a protein that causes AD, quite apart from the viral code itself.

  22. dearieme says:

    One argument for CVD being an infectious disease is that its rise and fall looks just like the corresponding curves for infectious diseases. Is there any sign of a decline in Alzheimer’s once you’ve corrected for age?

  23. bacillus says:

    @ Jai. Given that acyclovir is relatively harmless, I’m still willing to persuade my MD to put me on it for 2 months. Mind you, knowing my luck taking acyclovir after lifetime carriage of HSV will lead to more rapid onset of dementia.

  24. DrOcto says:

    This made me wonder how many other symptoms of aging are a result of accumlated DNA damage from viruses (as opposed to the accepted gradual accumlation of errors naturally alongside a failing repair system).

  25. Ty says:

    Once you have a cancer, you have a cancer no matter what caused it. We don’t treat cancers by blocking tumorigenesis. I think it’s silly to say we can treat AD with an antiviral agent. I am not to even mention how to show it in clinical trials.

    1. DrOcto says:

      People here weren’t talking about treating AD, they were talking about preventing it.

  26. JPeters says:

    I’m a long-time reader, coming out of the shadows for this. Does anyone suppose that either of the Gardasil vaccines (4 or 9), both of which are meant to provide protection against HPV6, might be a partial answer? I did a quick superficial search of the available info and it unfortunately doesn’t ever mention a specific strain of HPV6, but I’d be interested in getting vaccinated now – at age 35, no less!

  27. bacillus says:

    @Ty. The paper I originally linked to purports to show that antiviral treatments can indeed prevent/reverse early signs of “dementias”. Additionally, the data already exists to further test this hypothesis. Namely, is incidence of dementia significantly higher in individuals who have harbored HSV I or II for life or significantly reduced in those who have taken antivirals over a significant period of time. Long-term HIV survivors come to mind.

    @Jai. Newly diagnosed at aged 50+ doesn’t necessarily mean newly acquired. HSV can remain latent for 20+ years. I’ve never had a formal diagnosis since I’ve never sought medical treatment for my cold sores

  28. WhyNot says:
    Slightly related, and another possible big shift. It may be time to examine the interaction of these viruses with microtubules.

  29. E Ray says:

    I hope we do more research on HSV-6 and other herpes family viruses. Do we know much about how these are transmitted? Then we can look at groups of people who would be at higher risk for transmitting these and see what their rates of AD are–sex workers, nurses, dental hygienists etc…

  30. Michael says:

    herpes virus is not the cause of alzheimer’s disease. herpes does not cause the inflammation that causes the disease. herpes is a fairly easy virus. Alzheimer is caused by much stronger inflammatory fungi that our bodies cannot kill. how much time scientists can look at the microsop to understand it. people suffer terribly from this Disease . We need strong antibiotics to destroy FUNGI in the Brain . That is ALL.

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