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Scientists might be completely wrong about Alzheimer’s. It’s among the leading causes of death in the U.S., but despite decades of study, doctors still don’t know how to slow the progression of neurodegeneration and dementia, let alone stop it. And that might be because, according to a massive study published yesterday in the journal. Neuron, the prevailing hypothesis of how the disease starts is wrong.

Maybe it's not all about protein buildup. Maybe there are viruses, too. And if the findings hold up against further scrutiny, that could change everything.

The most popular idea for how Alzheimer's starts is the amyloid cascade hypothesis. It says the disease stems from the overproduction or accumulation of proteins called beta-amyloid, which clump together into plaques in the brain. These plaques lead to the formation of tangles of fibrous tau proteins, and ultimately cause the death of neurons.

The trouble is, pharmaceutical companies have been cooking up drugs that reduce amyloid-beta production or clear out plaques for years, and none of them have stopped or slowed the disease in people. So the researchers behind yesterday’s study decided to come at the problem from a different angle. Instead of starting with amyloids or any other idea about how the disease starts or progresses, they used mathematical models.

The upside of this approach is that it doesn’t require assumptions about what’s happening. Instead, it relies on massive amounts of data about everything, from the genes and their expression levels all the way to visible symptoms of the disease, to explain what’s going on. This method takes a lot of data, and they were able to get it through brain banks — collections of brain tissue samples from people who elected to donate their brains for research after they died.

Because they wanted to spot things that initiate Alzheimer’s, the scientists compared healthy brain tissue to those from people who had plaques and tangles in their brains but didn’t have symptoms yet. So they had the disease, but it was early on—that way, the team wouldn’t be misled by things that happen in the brain later as a result of the disease. And they specifically looked for networks of genes that were behaving very differently in these early Alzheimer’s brains and healthy controls, and for the genes that were driving those differences.

Turns out, many of these genes were also ones that get dialed up or down when you’re infected with a virus. So, much to their surprise, their data-driven approach implicated viruses. And while that might seem out of left field, the idea that microbes might be behind Alzheimer’s isn’t new — in fact, it’s been around for at least half a century.

Some scientists have noticed links between various infections and Alzheimer’s disease, like that some infections can cause plaques to form in animal models, or that certain microbes show up more often in diseased brains. These links were compelling enough for them to propose an alternate model for Alzheimer's: the pathogen hypothesis, which says the plaques are just part of the disease — not the cause. But the idea hasn’t gotten much traction in the field.

So as soon as the team from this new study saw a connection to viruses, they knew they had to dig a little deeper. They checked for evidence of more than 500 viruses in four different brain regions in over 600 brain samples. The results showed that two viruses in particular, which were types of human herpes viruses, were elevated in Alzheimer’s brains.

Despite the name, these aren’t the viruses behind genital herpes, and instead are most closely related to the strain behind roseola, a rash and fever common in young children. They screened brains from other brain banks, too—more than 900 brains all together—and those Alzheimer brains also had lots of these viruses. But they weren’t done.

By itself, the data they’d gathered was just another correlation. It might not mean anything. So they did a bunch of tests to see if the evidence, as a whole, was consistent with the idea that these viruses could play a role in Alzheimer’s—and it was.

The more genetic material people had in their brains from these viruses, the more severe the disease was. The team also found that certain small differences in people’s DNA might be allowing the viruses to do more damage. In other words, in their view, those at highest risk for Alzheimer’s are likely to be people who have certain genetic predispositions combined with a viral infection.

They even tried an experiment on mice where they removed one of the genes turned down by one of these viruses, and that led to an increase in brain plaques. So, the team did a lot of investigating, and the results strongly suggest that viruses are at least partially to blame for the disease. But it’s important to note that this isn’t proof of causation.

The researchers were very clear about that. So it’s way too early to declare war on herpes viruses to fight Alzheimer’s. For example, this might be a weird side effect that happens because Alzheimer’s somehow makes people more susceptible to brain infections really early on.

Or, it’s possible that the viruses are involved somehow in making symptoms worse, but aren’t the actual trigger of the disease. Basically, there are a lot of hints that viruses might be to blame in some capacity, but it’s not clear how this translates clinically. No matter what, the full picture is going to be complicated.

It’s entirely possible that what we call Alzheimer’s is triggered or progresses in multiple ways — so the viruses could be involved in some cases but not others. And maybe the person’s immune system matters, too. Either way, this new study means scientists have a lot to think about.

And since the researchers stumbled upon the viral link using an unbiased method, it may win over enough skeptics to get funding for more experiments, like a clinical trial. And that just might lead to a whole new way of thinking about Alzheimer’s—and eventually, ways to prevent or treat it. Thanks for watching this episode of SciShow!

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