Turns out, a great many viruses use low-density-lipoproteins (LDLs, of heart disease fame) to travel around the body, and some even enter our cells by binding to LDL receptors. The APOE gene, associated with alzheimers, binds and transports herpes in the brain and hepatitis viruses in the liver!
If I understand correctly, APOE helps viruses enter neurons. How does APOE4 behave differently than other isoforms in this regard? APOE itself isn't implicated in AD risk, just the APOE4 isoform. And I couldn't tell from your post or a brief lit search, what's the current thinking on the relationship btw APOE and amyloid beta?
I think APOE4 is associated with higher levels of beta amyloid but I don't know why. You mention a study showing beta amyloid traps herpes simplex? Is there a mechanism by which APOE4 drives more beta amyloid aggregation to fight viral infections, but as an unintended result leads to AD?
I've briefly followed some of the recent papers on a viral link to AD but haven't spent much time on it, your post has inspired me to do some more research!
* APO-E isoform, that predicts alzheimers risk, correlates with how much beta amyloid is present in the brain
* It also correlates with how much Herpes Virus is present : https://www.theatlantic.com/science/archive/2018/07/herpes-v...
"Readhead and his colleagues have shown that the more E4 copies someone has, the more HHV–6A and HHV–6B viruses they are likely to have in their brains."
* We also know that if you knock APOE out in a mouse, and then infect it, there is WAY less HSV penetration in the brain (see figure 1, and note that the Y-axis is logarithmic!) : http://jvi.asm.org/content/76/23/12394.full
* Also, APOE isoforms predict whether or not Hepatitis B virus will give you liver cancer. Note that its the E3 genotype that is risky for this, yet its the E4 genotype thats bad for Alzheimers. I take this to be evidence that hepatitis viruses and herpes viruses likely have different binding affinities to these two isoforms.
* Someone should do some drug screening to eliminate binding between known viral capsids and APOE variants. cough YC Bio
Would antiviral therapy be more effective that blocking capsid-APOE interaction? It's my understanding that blocking protein protein interactions is challenging, although inhibiting that interaction would be a nice specific way to block the mechanism
Alternatively, maybe we could train our immune systems to detect when a lipoprotein is transporting malicious cargo. Ideally, if we could realiably distinguish between healthy LDL particles and lipoviral particles, maybe we can find surface epitopes!
I wonder if the reason foam cells are forming in atherosclerosis is because the immune system suspects that they may be infected and carrying payloads.
The relationship btw HSV, APOE, amyloid beta and AD is certainly intriguing but it seems quite messy at this point. Would imagine there's a lot of work to do to unravel the mechanism before we get to the point where we can think about how best to drug whatever target emerges. Unfortunately mouse models in AD are terrible, so studying the biology may be very tough, although it seems iPSC derived neurons are proving to be decent models.
As someone who has, on more than one occasion, called out top-posts that were flat-out wrong, but conformed to HN's biases (I was 100% certain of this because the posts concerned either my area of expertise or my first-hand experiences) - I will disagree with you. The occasions made me wonder about the other HN posts where I'm not an expert.
But it's a little like that saying about democracy being "the worst thing ever -- except for everything else". In spite of HNs serious delusions about how objective etc it is, it still remains vastly more objective, rational etc than anything else I've found.
Freudian autocorrect error!
I once told my boss, who studies sociopaths, that I have "sociopuny" ... and she facepalmed harder than you can imagine .... This one wasn't intentional. I have a problem.
EDIT: from the downvote, it seems that I've already been PUNished ...
Do... your ... worst HN!
This newer theory is that the cause of the amyloid build-up is an immune response to the herpes virus increasingly infiltrating the brain (as you get older the blood/brain barrier that protects your brain from infections weakens) so a possible treatment is to try and reduce the levels of herpes infection rather than attacking the amyloid protein which is your body's immune response to the herpes infection.
The APOE4 gene is infamous for increasing amyloid production and being a major risk factor for early-onset Alzheimers and so carriers of the gene are often used in studies to see the effect of treatments. (@subcosmos below has a good explanation of what this gene actually does)
How does this help crossing the BBB? Can you give a citation?
Some VERY notable statistics mentioned in the paper : "Such studies have revealed endemic infection rates of 31% in children aged 6–14, rising to 49% in adults aged 14–49, and to a high of 80–90% in the population over 65. In one study of 40 autopsied TGs, HSV-1 sequences were amplified from DNA or RNA extracted from 81% of TGs from demented subjects, and 74% of controls"
I blogged about these connections here, for I think that this retrograde transport phenomenon might explain Tau phosphorylation, which is a secondary hallmark of Alzheimer's and other dementias : https://medium.com/@InfinoMe/cholesterol-have-we-shot-the-me...
Expanding further: the blood brain barrier is made of cytoplasmic expansions of astrocytes in the central nervous system. The T-shape sensory cells are part of the peripheral nervous system, their axon ends up in the encephalon.
I think this is still an open question. Beta amyloid proteins may not be the root/fundamental cause.
Most of the latest studies are showing a reduction in Alzheimer’s risk after treating patients who have some form of herpes with anti-viral medication.
"Among the Tsimane as a whole, adults with APOE4 got poorer scores in these tests. But when the team focused on the people with high parasite levels, they saw that the APOE4 carriers had better mental skills, even outperforming APOE3 carriers who were parasite-free."
Further high signal discussion on Reddit that goes into more depth: https://www.reddit.com/r/science/comments/8z1lg0/hpv_vaccine...
The relevant quotes from the article:
"The two groups were followed for almost a decade, between 2001 and 2010. In the herpes group, the risk of dementia was over 2.5 times higher than in the control group.
Significantly, the study also revealed that aggressive antiviral treatment reduced the relative risk of dementia by 10 times."
Looking at Wikipedia "According to the World Health Organization 67% of the world population under the age of 50 have HSV-1." and according to the source there 11% have HSV-2. There's probably some good amount of overlap between the two, but we have somewhere between 67 and 78% of the population with some form of herpes. In any case the "general population" is closer to having herpes than not having herpes, so we'd probably arrive at a factor somewhere closer to the 10x.
According to the CDC "54% of persons aged 14 to 49 had HSV-1 infection" 10X for 54% is a big thing.
"It should be stressed that [...] those treated were the few rare cases severely affected by HSV."
I'm guessing it's acyclovir since there's a link to another page on the site in the "Related Coverage" section.
Source: I work in natural products chemistry.
PS: On the other hand, if something kills those things..
Iodine has been claimed to induce apoptosis in a number of cancer types while remaining harmless to normal cells.
I'm only a make-believe biologist.
Obligatory mention of how piperine (black pepper extract) is necessary for bioavailability.
There’s no way to tell from reading the article, you’d need to read the paper. From the article it’s not clear whether it’s the 2.5x increased risk that’s decreased to 1.25x, or whether people on antiviral meds had a lower risk than the control group (0.25x).
It wouldn't occur to me to see a doctor over a cold sore and if I did my GP would probably laugh me out of the office.
So maybe (here's me grasping at straws) these people had herpes of a severity completely unlike the millions that buy cold sore cream at the supermarket. Or they had symptoms for the very first time, which would be extremely unsual as well considering they were all over 50.
None of that takes away from the surprising effect of the anti-viral treatment on Alzheimer's, but I think the size of the effect may be related to the unusual severity of these particular herpes outbreaks.
The typical set doctors look for are HIV, Syphilis, Gonorrhea and something else that escapes me right now.
So that's why I think the people included in that study must be somewhat atypical.
We all get exposed to chickenpox and most of us are latently harboring it.
I wish I understood all of the herpes isoforms better.
Background: HSV1 is commonly known as cold sores. Some people get them in their mouth, or on their lips. Most of the population don't develop any symptoms.
This link between HSV1 and Alzheimer's could be big business. The numbers are wildly divergent, but it sounds like a sizable chunk of the US population has HSV1. I've seen estimates from 20% to 80%. Even if it's the very conservative 20% number, that's still a big market.
The skeptic in me (his name is David) is suspicious of this article precisely because it has the potential to be such a big market. Case in point, there's a link to some HSV1 medicine at the bottom of the article. I wonder if they have an affiliate marketing arrangement with the makers of acyclovir. Tangentially related, I think that this article is on the front page of HN precisely because HSV1 is so widespread. For example, if another article discussed a cure for Alzheimer's, but that article involved some rare condition that does not affect the general population, would that article hit page #1?
With that said, I think our society's lax approach to HSV1 is bizarre. In Sex Ed, I didn't get any education around the fact that kissing people and sharing drinks can spread a virus. After reading quite a few articles on the virus, I got the impression that STD researchers don't really know much about it. I could be wildly incorrect about that last point, I'm not a medical expert. It's just the general impression I got when trying to understand HSV1 from an STD perspective. For example, it's been common wisdom for a long time that, if you have HSV1 (cold sores), then you can't get HSV2 (genital herpes). But the reality seems to be more ambiguous than that. Apparently there was a fairly recent study mentioning that college students who have HSV1 performed oral sex on their partners and transferred HSV1 to the partner's genitals. Or something like that.
Long story short, although I'm skeptical of the business incentives around associating HSV1 with something as scary as Alzheimer's, I welcome more research around understanding HSV1.
If this is proven, I imagine almost all the funding for Alzheimers getting diverted to curing HSV1. That would suck for one group of researchers while being a boon to another - as well as half the world population with HSV1. Shingles (adult chickenpox) is also in the herpes family.
If you read about the history of the virus, supposedly in the past most people figured they'd get it (both variations) sooner or later and didn't particularly care. The stigma, especially of HSV2, allegedly started mid 20th century when acyclovir / zovirax came on the market and the company who created it needed a reason to push people to start using the medication. Nobody wanted to at the time, as HSV wasn't a big deal. However once you call people who have it "dirty" and make it shameful, the sales go up. Now you want to suppress outbreaks and potential spreading at all costs. Similar to AIDS in the 80s, in the US people won't even hug you if news leaks that you have HSV2.
Also amusing that, in the state of CA, receiving HSV (1 or 2) to the genitals from someone of wealth is a great source of compensation. Most of the money you'll receive from the civil case will not be for the medical treatment, it will be because of the "psychological damages and impact to lifestyle" from suddenly becoming a social pariah. Like you said, why this would be suable is not obvious. If 80% of the population has HSV1 and you transmit it to the genitals through oral sex, you're now a 2 year-long (statute of limitations) juicy target for a lawsuit. People of means have lost millions of dollars to this. Everybody having sex becomes a ticking timebomb of legal extortion. Better have your partners sign a consent form.
Also, if you do disclose, you better have in it writing. If there's no evidence of STD disclosure, you can still be sued, and then it's he said vs she said (or pick your permutation of genders) and it's your two reputations competing for who's more trustworthy in court and can have the upper hand. That disclosure can still cost you.
Lawyers will always advise you to have disclosure confirmation in writing (email or paper is best, text might be still ok).
I don't profit from spreading these ideas. I'm just one of the head data scientists at one of the top dementia labs and I'm tired of longevity-based research taking so friggin long. I also have zero desire to spend a year writing this up only to pay some scientific journal top-dollar so they can paywall it. Putting it up on Medium hopefully saves more lives faster.
I guess I took inspiration from the viruses and snuck my medium post on an innocuous buzz article that is exploding on social media now. Sorry not sorry :p
My only goal was to inject some skepticism and awareness around why this particular article might receive more attention.
The linked papers however seem to point to the true hero of this story, a scientist who has apparently been taking shit for decades for her theories. Looks like she was right after all : https://www.theatlantic.com/science/archive/2018/07/herpes-v...
Ruth Itzhaki from the University of Manchester notes that “hostility or derision occurred with most of my papers on this topic, and many people simply ignored them.”
I predict she will be a Nobel recipient
As someone at hopefully an early enough age who hasn't had any (known? -- since there's never any certainty with it) outbreaks, I'm wondering whether getting such a prescription based on family history at this point would be well advised. It'd also be neat exploring the side effects and seeing if that's a worthy trade, but it sounds like it probably is.
Biohacking is fun.
If the parent means, 'it sounds like herpes treatment will probably reduce my risk of Alzheimers', it is almost certainly wrong. That is a dangerous conclusion of amateur medical research.
The existence of a couple studies or analyses correlates very poorly with an effective treatment. Look at all the problems of the drug industry and scientists, with all their knowledge and resources, when trying to convert far more proven research into effective treatments. Even when there are effective treatments, they often need to be carefully implemented in terms of drug design, delivery, dosage, etc.
> Biohacking is fun.
That's a sci-fi fantasy. If someone reading this thinks it's "fun", they have no idea what they are talking about and should stop immediately.
Not sure what you mean by “there’s never any certainty with it.” You can get tested for HSV1 as part of an STD screening. You just need to ask for it.
The less frequent side effects of aciclovir raw are interesting. Likewise for the prodrug valaciclovir (Valtrex). Some of these sound like they're a result of some level of impact on brain function. I can't help but wonder if there's any relation.
But you're right. The adverse effects here don't seem like much of a deterrent in the face of elevated risk.
Be careful with those numbers. I would neither fully trust it nor dismiss it. But these genetic heritage companies have been known to get it wrong, a lot (and very wrong in some cases).
Although having the good version of APOE doesn't mean you'll never get it, and having the bad version doesn't mean you're guaranteed to get it. The odds do shift quite a bit, though.
Well, having the bad version of the genes certainly doesn't guarantee anything if you don't live long enough too. Only 5% of all people who have the disease have developed symptoms before the age of 65 after all, while average life expectancy of men in the US is at 76. It's very well likely to be predisposed to diseases like these and not develop symptoms because something else killed you before it could show up.
So you should definitely hesitate until you fully grok the numbers.
My mother has dementia, so this issue hits home for me, btw. But I don't see myself taking some medication in order to try and prevent something I may never end up getting. Herpes medications are not vitamins, if you get what I mean.
I wonder if there could be a link between HSV and the development of ADHD in early childhood. Or perhaps other mental dysfunction?
Furthermore, I wanted to add that there are a lot of studies that indicate lack of sleep as a risk factor for Alzheimer's. Lack of sleep is also one of the biggest causes of HSV reactivation and outbreak.
I'd be interested in knowing if Lysine supplements have similar effect to acyclovir. The amino acid has a well studied suppressive effect [1, 2].
I'm going to email some of these authors to inquire.
I believe this is against the GDPR, but need to make a complaint against them.
Arguments why it is against the GDPR, if you can display the text to a googlebot and you will do no change to the structure of the document that is the main purpose of coming to the site then it is not GDPR compliant to deny someone access to the resource based on the argument that they need to do tracking to make the particular resource work.
In other words they are quite clearly lying and should be fined.
There should be some general make GDPR complaint tool where people can go, say where they are from, write what site complaining about, and it shows you similar complaints for you to add yourself to, or to send a new complaint. Then it packs them off to the relevant organizations to handle the complaint. Probably someone has already made this tool but I don't know about it.
Regarding the JS, I have come to the same conclusion. On a large amount of news websites, I have everything blocked (CSS too) with some element hiding rules to remove the strange menus and whatnot. The content you care about on such a site is the text, with maybe one picture. Almost nothing is lost by refusing everything else.
> These authors report that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing SD. Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group.
And the article:
> The latter study — deemed "most important" by Profs. Itzhaki and Lathe — examined 8,362 people aged 50 and above who received a diagnosis of herpes simplex virus (HSV) infection, as well as a control group of 25,086 age-matched healthy people.
Within the HSV1 population, a small amount happened to get aggressive treatment at some point. It’s not clear whether they got treatment at any point in their life, or if they got treatment after the study began (meaning they got treatment at age 50 or later). This minority happened to have much less chance of Alzheimer’s later on in life.
In regards to the timing of the treatment, my guess is that they got treated upon outbreak, since it said that they were severely affected. They would get treatment when they were in the most pain or discomfort.
It sounds like only a small minority of the 8K people in the HSV group got treatment.
Edit: I must have gotten confused. I was thinking they talked about HHV6/7 as I saw another discussion about that recently https://news.ycombinator.com/item?id=17366591 From another source: "Nearly 100% of humans are exposed to HHV-6 by the age of three"
Edit 2: Although HSV 1 is also apparently very common in adults. 2 out of 3 have it.
Results aren't consistent, but I would be surprised if the latest round of texts didn't spur further examination.
And Scientists claim herpes, chlamydia and other infections could be responsible for Alzheimer;