Alzheimer's, Parkinson's, and dementia are some of the most tragic consequences of aging.

And we’ve had to accept them as inevitable, because we’ve had no other choice. But that might be changing, because these conditions  could have a surprising cause: common infections like the flu.

In other words, these diseases may not be  something we have to accept as part of getting older -- we might be able to prevent them. Now, to be clear, the flu virus does not suddenly give people Alzheimer’s. It gives people the flu.

And Alzheimer’s is not infectious. You can’t catch Alzheimer’s the way you can catch the flu or mono. That’s because Alzheimer’s,  Parkinson’s, and dementia all belong to a family of chronic diseases that are caused by a build-up of protein gunk in our brain and nervous system.

They’re called neurodegenerative diseases, or NDDs. But when researchers look back into history, they start to see some odd trends. A few years after big virus outbreaks like the 1918 flu pandemic, they would keep seeing surges in “Parkinsonism,” or symptoms like Parkinson’s.

Since then, a constellation of links between infections and NDDs has been growing – it seems like when a severe infection happens, an NDD becomes more likely to follow. But those links are both really  hard to pin down and hotly debated. Here's how we're connecting the dots and maybe, just maybe, kicking some of our most devastating diseases to   the curb. [INTRO] Establishing for sure that the flu or mono causes Alzheimer's is super  ridiculously difficult.

Like I said, the flu virus causes the flu, the mono virus causes mono, and the shingles virus causes shingles. Well, and chickenpox. So saying they also cause Alzheimer’s might seem like a totally wild take.

We’ll get to how it might happen in a little bit, but the main thing epidemiologists want to see is: Does X cause Y? They can worry about the  how once they know the what. And, yes, viral infections might cause NDDs.

At least, an association between the two is starting to show up everywhere you look. So far, the links are still fuzzy. But there are very specific elements researchers know to look for in order to prove that a specific factor causes a specific disease.

The first thing you have to  do is nail down the timeline. It seems obvious, but historically, one of the most important and challenging parts of figuring out whether infections cause NDDs has been establishing that people had the viruses first. Because we can’t say viruses are causing NDDs if the patients already had Alzheimer’s before they got infected.

That isn’t how time works. Luckily, figuring this out got a whole lot easier with the rise of electronic health records. In 2023, a study published in the journal Cell analyzed health records from over three hundred thousand people thanks to a massive database in Finland.

That’s a lot of people. They identified patients with  a bunch of different NDDs — Alzheimer’s, dementia,  Parkinson’s, ALS, and so on. Then, the researchers looked up to 15 years back in their record for any severe viral infections.

We’re talking flu, mono, pneumonia, herpes, stomach viruses, shingles, and more. Then they compared that group to people who also had an infection but were never diagnosed with an NDD. The results were striking.

They found 45 viral exposures which significantly increased risk for developing an NDD in the future. And that’s interesting. But if the research team stopped there, their results probably  wouldn’t be super trustworthy.

See, both these infections, like flu, and many NDDs, like Alzheimer’s, are all really common. And when you take a bunch of really common things and do some statistics at them, the math is sometimes going to come up as a match by pure, random chance. A tiny bit like those infinite monkeys  coming up with the text of Hamlet.

It’ll happen eventually. In statistics, this practice is called “fishing” because you’re casting a really wide  net to “fish” for significant results. That means some of those 45 associations were probably not actually real.

So, the team turned to a different  huge database of health records, this one from the UK. They successfully reproduced 22 of the original 45 associations from that dataset, suggesting there might well be something to them. The strongest association was  between viral encephalitis, a virus causing inflammation  in the brain, and Alzheimer’s.

It showed that being hospitalized with encephalitis increased someone’s risk for developing Alzheimer’s by 22 to 30 times. Reproducing their findings with data from a different country is a great start, but what is maybe even more persuasive is the number of other researchers that have independently  come to the same conclusion about viruses and NDDs. Researchers have found similar links between mono and multiple sclerosis, mono and Alzheimer’s, and flu and Parkinson’s.

So, the evidence is building for links between viruses and neurodegeneration, but that’s still not rock solid proof that viruses are causing neurodegeneration. It’s just that this connection  is really hard to study. These NDDs seem to pop up between 1 and 15 years after the infection.

That’s a long time to keep track of hundreds of thousands of people. The gold standard of proof would be some kind of clinical  trial where we’d find people, infect them with a virus, and then watch them in a controlled environment to see if they develop Parkinson’s or something. And while a study like that has actually been done successfully in rats, you cannot do that in people and should not try.

So public health researchers  instead use real world data to make observations. For instance, several studies have shown that getting vaccinated for the  flu, shingles, and pneumonia can reduce the risk of developing Alzheimer’s and Parkinson’s. That tells us a few important things.

First, while vaccines don’t  prevent all cases of infection, they can dramatically reduce the  severity of those infections. And that’s important, because that big study we were talking about earlier with  hundreds of thousands of people — that was looking at hospital data. And since you usually don’t  check into the hospital when you have the flu, that means we’re talking about severe infections.

Vaccines are available for several of the viruses they looked at including  flu, shingles, and pneumonia. And they’ve all been shown to reduce infection severity or rates of hospitalization. So it could be getting severe infections leads to higher odds of  developing an NDD later in life.

It also means we may be able to  prevent people from developing NDDs with a few safe, routine shots. So the question remains, if viruses cause NDDs, why and how do they do that? Why would a stomach virus so nasty you end up in the hospital cause problems for your brain?

And not right away, but 15 years later? Having a plausible explanation  is not strictly necessary for establishing that viruses cause NDDs, but it does make researchers’ job easier when you get to the prevention part. So, to start off, it’s not unheard of for viruses to cause a chronic, non-infectious disease.

Human papillomavirus is well known to  cause cervical cancer, for example. But we’re looking at a  bunch of different viruses – flu, shingles, mono, herpes — leading to a bunch of similar NDDs. It’s weird that they seem  to end up in the same place.

It could happen a bunch of ways and  might be different for each virus, but here are two of the explanations  researchers have put forward. First, remember that all NDDs are caused by a build-up of protein  gunk in our nervous system. And second, all of these  viruses can be neurotropic, meaning they can enter and infect cells in our brain and nervous system.

Of particular note is herpes, or HSV-1. Over 60% of the adult population in the US is estimated to have herpes. Most of the time you hear about herpes it’s because of the painful  sores it can periodically cause on people’s lips and eyes.

In between flare-ups, the herpes virus lays dormant in our peripheral nervous system. Tons of things, from stress to sunlight — and even other infections — can reactivate the virus,  producing more baby viruses that travel down to the  skin and cause sores again. But those new viruses can also  migrate the other direction from the nerves in our skin up to the brain.

HSV-1 infections in the brain are  usually completely asymptomatic, but even mild brain infections can be harmful and HSV-1 seems to linger … forever. And in mice, anytime those  dormant viruses re-activate, they for some reason ramp up  production of the same toxic proteins that make up the plaques in Alzheimer’s patients, essentially accelerating neurodegeneration. Since both herpes and all  those other viruses are common, severe bouts with the flu or shingles may be repeatedly triggering  mild herpes infections in the brain, which could help explain why NDDs are correlated with so many different viruses.

So… it’s all herpes’ fault. Maybe. The other proposed mechanism has to do with the molecular cause of NDDs.

One thing viruses and NDDs have in common is that they both make big  protein complexes in our cells. For viruses, those complexes are new baby viruses, but in NDDs they’re globs of smaller proteins all stuck together in our nervous system. For viruses to replicate, they need to hijack our cellular machinery to assemble new viruses.

But it’s possible the changes they make to our cellular machinery could linger even after the viruses stop replicating. The faulty cellular machinery could, you might say, get confused. It’s now programmed to assemble proteins into new viruses, but it’s all out of virus.

Instead, they might accidentally start globbing human proteins together… improperly creating those  harmful plaques that cause NDDs. One study, which hasn’t been through  the peer review process yet as we’re writing this, does present some early  evidence supporting this idea. The study shows that a drug that was originally designed to  interrupt the assembly of HIV viruses can also slow the assembly of  plaques in patients with ALS.

So, maybe those plaques are being put together in a similar way, and the drug is resetting the faulty machinery. These ideas require further study, but they lend some weight to the notion that viruses are causing NDDs. All in all, while it’s still up in the air, the growing body of research certainly checks a lot of the  boxes epidemiologists look for when declaring a “causative relationship.” And we might get clarity on this  relationship in the coming years.

The world is reeling from the COVID-19 pandemic caused by SARS-CoV-2, a virus that can infect the brain. And if severe viral infections  really do cause NDDs, then we would expect to see an uptick in Alzheimer’s and Parkinson’s over the next 10 to 15 years. Some papers suggest it’s already happening, but like all science, we need to wait for many researchers to come to that same conclusion before we make that call.

Time will tell. Now maybe this seems like terrible news. We all get the flu!

We all get mono, and we all get herpes! So how does knowing they might be causing NDDs make any difference? Because knowing that viruses may be partially causing some of the most devastating diseases humans experience empowers us to find solutions.

We’ve learned that vaccines for common viruses seem to protect us from NDDs. Those vaccines prevent severe infections, and severity appears to be a factor. There are also other ways to reduce the severity of some infections – like Tamiflu for flu, or Paxlovid for COVID-19.

And while not all of these viruses have  vaccines yet, they’re working on it. For all of history, Alzheimer’s, Parkinson’s, and dementia have felt like  almost unavoidable problems we have to accept as we age. What if that’s not the case?

What if these heartbreaking diseases have such easy-to-tackle causes that we could be on the  verge of getting rid of them… at least some of them? It’s not going to happen  next year, or in five years, but if these associations with  infections turn out to be real, we suddenly have a massive toolkit for dealing with neurodegenerative diseases. Vaccines and treatments that we already know are safe and effective.

C’mon, science. Give us this one. [ OUTRO ]