Quirks & Quarks

Have researchers been wrong about Alzheimer's? A new theory challenges the old story

The protein that forms Alzheimer's plaques might be trying to protect your brain against infection

The protein that forms Alzheimer's plaques might be trying to protect your brain against infection

A woman suffering from Alzheimer's disease. Scientists are starting to question what might be triggering the onset of the disease in the first place. (SEBASTIEN BOZON/AFP/Getty Image)

For more than two decades, the conventional wisdom about Alzheimer's disease has been that the plaques in the brain that lead to the disease were caused by a protein that went rogue.

The problem with this theory is that nobody has been able to explain why this protein, the amyloid-beta peptide, caused these plaques to begin with. What's more, none of our attempts to fight these amyloid plaques have led to any improvement for dementia patients.

According to a new theory that's gaining traction in the Alzheimer's research community, these proteins may not be the villains we've made them out to be. 

"It turns out that [amyloid-beta proteins] form [plaques] because they're trying to help us. They're trying to fight an infection," said Robert Moir, an assistant professor of neurobiology at Harvard Medical School and the Massachusetts General Hospital.

"The Alzheimer's disease dementia that comes after years of this battle, are something like collateral damage from their actions. But it's not that it's intrinsically bad what they're doing. It's just that if you keep doing it for long enough the amyloid that is generated in this battle starts to become a problem in itself."

In fact, [the amyloid-beta protein] was 100 times better than penicillin at killing some pathogens.- Dr. Robert Moir, Massachusetts General Hospital

If this theory, which Moir outlines in a review article published in the December issue of the journal Alzheimer's & Dementia, proves true, it could mean researchers' current strategies to combat the disease — fighting the plaques — is misguided.

Two clues that inspired this new theory

Moir said the first indication he had that the amyloid-beta​ proteins might serve a biological function was when he discovered another protein, called LL37, which acts like an antimicrobial agent and yet showed many structural similarities to the amyloid-beta protein.

"It turned out that was a natural antibiotic that was protecting you against infections."

The second clue for Moir was if amyloid-beta was really a pathological protein, then why did evolution conserve it across so many species?

In fact, it's pretty hard to find an amyloid plaque that doesn't have some sort of microbe in it.- Dr. Robert Moir, Massachusetts General Hospital

"This is a very ancient protein," said Moir. "It's remained unchanged for 400 million years and most vertebrates actually have it in their brains."

Even fish and reptiles have the same amyloid-beta​ protein in their brains that we do.

"This is telling us this protein is probably doing something very important if it's going to be preserved for such an extraordinary length of time unchanged. And the other thing it's saying is that its behaviour, this ability to form amyloid, is most likely right at the core of whatever that useful function is. And that's in stark contrast to the reigning idea which is that [amyloid-beta] just forms amyloid because it's bad and that [amyloid-beta] does nothing except cause trouble."

Testing amyloid-beta protein's antimicrobial activity

The first thing Moir did to test his theory was to add the amyloid-beta protein to microbes in a test tube to see whether or not it killed them. It did.

"In fact, it was 100 times better than penicillin at killing some pathogens," said Moir.

He and his colleagues spent the next few years testing the proteins to see if they also show antimicrobial properties in animals, as well as test tubes.

We ended up with a remarkable number of models, six in total, all the way from cells in culture, fruit fly, little nematode worms, to mice. And it was all consistent with protection from infection.- Dr. Robert Moir, Massachusetts General Hospital

"We ended up with a remarkable number of models, six in total, all the way from cells in culture, fruit fly, little nematode worms, to mice. And it was all consistent with protection from infection."

In one of Moir's recent studies, they tested what happens when the amyloid-beta meets the Herpes simplex 1 virus, which he said is found in many brains of people who had Alzheimer's disease.

"What we saw was when our animal models were given herpes infections in their brain, a-beta rose to do battle. And the aftermath of that battle was that they trapped the viruses in the amyloid, essentially neutralizing it. And then they generated a huge burst of what is essentially bleach. And that killed the microbes."

Once the protein begins forming the plaques, the cascade of events becomes a bit like an avalanche. The plaques form tendrils, like threads, that surround the infection and start to build up.

A woman suffering from Alzheimer's disease holds the hand of a relative. By the time Alzheimer's sets in, Moir says it's too late to go after the amyloid plaque. (SEBASTIEN BOZON/AFP/Getty Images)

"They literally formed these long fibres [resembling a] fishing line," said Moir. "And the analogy here is pretty close, because they actually hook onto the microbes and reel them in pulling them into this mess."

If the amyloid plaques continue to build, then the brain's helper immune cells that usually tend to the neurons become overexcited.

"If [those brain immune cells] see too much amyloid, they switch to busywork warriors and these guys then start attacking everything that moves — including, unfortunately, neurons. And once that happens it's very hard to switch them off. They just keep going and eventually the damage to us starts to make an impact on our ability to think. And that's really what drives this process. And so you can actually take the amyloid away, but they're not going to stop being inflamed. It's a bit like arthritis."

Reaction from scientific community

Moir's idea has met some strong resistance in the research community.

Peter St. George-Hyslop, the director of the University of Toronto's Tanz Centre for Research in Neurodegenerative Diseases who also studies Alzheimer's disease, said he's waiting for someone to replicate Moir's findings. And until then, "healthy scepticism is still in order here."

Another Alzheimer's researcher, Todd Golde a professor of neuroscience and director of the McKnight Brain Institute at the University of Florida, said he thinks Moir's theory is an intriguing and creative approach to looking at what the function of the amyloid-beta protein might be.

Healthy scepticism is still in order here.- Peter St. George-Hyslop

He added, however, that "a lot of times we could observe things in an ex-vivo system or some simple model system and it may not translate to what's really happening in humans."

Moir said there's a large body of evidence out there that microbes of various types are associated with amyloid plaques in people. "In fact, it's pretty hard to find an amyloid plaque that doesn't have some sort of microbe in it."

Different strains of the herpes virus has been found in human amyloid plaques. So have different fungal pathogens even the Lyme disease bacteria.

What this could mean for how we fight Alzheimer's

Moir said in the shorter term, instead of trying to break up the amyloid plaques in the brain, when it's too late in the progression of the disease, he thinks a more effective way to treat Alzheimer's is to target the inflammation the plaques cause.

"For people with Alzheimer's disease, that's probably looking like the best hope," he said.

In the long term, Moir plans to try and identify exactly which microbes are responsible for triggering the cascade effect that leads to Alzheimer's.

"You may be able to use anti-infectives or indeed vaccines to limit the chances that some microbe is going to get into your brain and trigger this whole thing," said Moir.

"That's where the future sort of focus for us is going to be — and that is trying to work out what pathogens may be triggering it. And there's gonna be more than one and that's the bottom line on that."


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