In 1907, the German psychiatrist Alois Alzheimer published a description of a 50-year-old woman who suffered from memory problems, hallucinations, and delusions. In the woman’s brain, Alzheimer noticed unusual lumps, or “plaques,” which “were caused by the deposition of an unusual substance.” Eight decades later, the mystery substance was finally identified as a protein called amyloid beta. Though small, it can accumulate in large clusters that are somehow toxic to neurons. Those harmful plaques are one of the hallmarks of the disease that bears Alzheimer’s name.

What amyloid beta normally does in the brain isn’t clear. Robert Moir, a neurologist at the MassGeneral Institute for Neurodegenerative Disease, says that many researchers have cast it as a villainous molecule with no beneficial function.  “It’s just bad, bad, bad,” he says. “But it has become increasingly obvious that this isn’t true.” Moir thinks that amyloid beta has a more heroic role, as a foot soldier of our immune system. It protects neurons from infectious microbes—and from herpes viruses, in particular.

William Elmer, a member of Moir’s team, demonstrated this protection by injecting the common herpes virus HSV–1 into the brains of two kinds of mice: normal rodents and ones that were genetically engineered to produce high levels of amyloid beta in their brains. The latter were better at resisting the viruses. Elmer then got similar results when he injected a different herpes virus, HHV–6, into human cells growing in a dish.

Amyloid beta protects against these viruses by latching onto them in large numbers, imprisoning them in self-assembling cages. That’s typically a good thing, but Moir argues that if the process goes on for too long, it builds up to the problematic plaques of Alzheimer’s. According to him, amyloid beta is still at the heart of the Alzheimer’s story, but it isn’t the villain. “In our model, Alzheimer’s is caused by amyloid beta’s reaction to something else, and most likely some kind of infection” like herpes, he says.

Moir notes that amyloid beta also exists in most other backboned animals. The protein first evolved around 400 million years ago, which is also roughly when the herpes virus family first appeared on the scene. “It’s clear that herpes and amyloid beta have been slugging it out since before there were insects,” Moir says. “One’s tuned to escape and the other to capture.”

This gives credence to the long-dismissed idea that viruses—and herpes, in particular—are involved in Alzheimer’s in some way. That’s not to say that the disease is contagious, nor that everyone with herpes infections is at risk. After all, HSV–1 and HHV–6 are extremely common. Two in three people have been infected by the former, which mostly causes cold sores. Almost everyone has encountered the latter.

In the past three decades, more than 100 papers have described correlations between the presence of HSV–1 and the risk of Alzheimer’s. 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.” But evidence continues to grow. Most recently, Ben Readhead and his colleagues at the Icahn School of Medicine at Mount Sinai showed that two herpes viruses, HHV–6A and HHV–7, were more common in the brains of Alzheimer’s patients than in those of healthy people. The team confirmed this in three separate groups of patients. And they found that the more abundant the viruses, the worse the patients’ symptoms.

It’s possible that these herpes viruses are mere hitchhikers that are more likely to infect brains that are already deteriorating. But Readhead also showed that they can influence the activity of many human genes, including an unexpectedly large number that affect the risk of Alzheimer’s and the progression of the disease. “Some of these viruses are interacting with genes that are in the middle of known Alzheimer’s biology,” he says.

For example, the most infamous Alzheimer’s-related gene is ApoE. It comes in three forms, and the E4 version is the problem. People with one E4 copy have a threefold-higher risk of Alzheimer’s than those who have no copies, and those with two E4 copies have up to a twelvefold-higher risk. 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 can’t make any causal inferences” from these studies, cautions Maria Carrillo, the chief scientific officer of the Alzheimer’s Association. “Their findings don’t prove the viruses lead to Alzheimer’s progression, but there is a relationship, and we need to understand what herpes viruses are doing in the brain.”  

Moir suspects that as we get older, herpes viruses take advantage of our weakening immune systems to spread from other parts of the body into the brain. Amyloid beta rises to meet them in battle, and deposits of amyloid-entrapped viruses start to accumulate in the brain. This goes on for years, and slowly but surely leads to the other hallmarks of Alzheimer’s.

This is all conjecture for now. It’s also possible that herpes simply exacerbates a process of amyloid accumulation that has been triggered by something else, or that other changes in the brain allow long-standing herpes infections to run amok. “It’s going to be more complicated than a simple case of an infection leading to disease,” Moir says.

“These studies suggest a possible role of viral infection as a contributing factor to Alzheimer’s disease,” says Li-Huei Tsai, a neuroscientist at MIT who studies the disease. “But it remains to be seen if drugs used to treat herpes-virus infection can be protective against Alzheimer’s.”

Hints that they can already exist. One study published earlier this year tracked the health of about 78,000 Taiwanese people, half of whom had been diagnosed with shingles within a 16-year period. Shingles is caused by a herpes virus called VZV, which also causes chicken pox in children. Among adults, the study found that people with a recent shingles flare-up had an 11 percent higher risk of developing dementia than healthier peers. And strikingly, those who were treated with anti-herpes drugs had a 45 percent lower risk of developing dementia than their untreated peers.

A second Taiwanese study looked at more than 8,000 people who had been recently diagnosed with HSV–1. Over the next decade, those people were 2.5 times more likely to develop dementia than uninfected peers. But again, that risk fell by 80 percent among those who had been treated with anti-herpes drugs. “That’s perhaps the strongest epidemiological data to emerge so far,” Moir says.

These drugs would have to be tested in clinical trials. And even if they can reduce the risk of Alzheimer’s, “they aren’t very pleasant and you can’t treat everyone,” Moir says. “The problem is how do you find people who have a herpes infection that warrants targeting with medications? It’s not clear.”

Scientists have spent decades trying to develop treatments for Alzheimer’s by creating drugs that get rid of amyloid beta. This approach has been catastrophically unsuccessful, with hundreds of clinical trials and nothing to show for them. Perhaps a better understanding of what amyloid beta actually does, and how it interacts with viruses, could lead to better strategies for beating Alzheimer’s—a disease that affects almost 30 million people worldwide.


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