Don’t ignore potential microbial causes of Alzheimer’s and other chronic diseases, researchers say

SAN FRANCISCO — On a day when pharma giant Eli Lilly announced positive results from a clinical trial of an Alzheimer’s drug that clears knotty clumps of protein from the brain, researchers at STAT’s Breakthrough Summit discussed another promising though preliminary approach to treating the disease: targeting viruses and bacteria.

The conversation on Wednesday centered around decades of evidence linking herpes simplex virus type 1, or HSV-1, to Alzheimer’s. Studies in human brain tissue, neural stem cells, and mice have suggested that this common virus, best known for causing cold sores, might trigger the deadly and devastating neurological disease.

This all raises the tantalizing possibility that antiviral therapies and vaccines could help treat or prevent Alzheimer’s. And there are now clinical trials testing this hypothesis.

“This would be huge. If you tell me I can get an extra dose of a vaccine that can reduce my risk of Alzheimer’s by 30%, then I’m walking off this stage right now and going to get it,” said Alberto Ascherio, an epidemiologist at the Harvard T.H. Chan School of Public Health.

But that’s not yet the case. And Ascherio, who led a landmark study published last year suggesting that Epstein-Barr virus can trigger multiple sclerosis, stressed that these findings about HSV-1 still need to be conclusively confirmed.

“Is this true or not?” he said. “It’s true in [a dish]. It’s true in animal models. I want to know if it’s true in humans.”

The Alzheimer’s field has for decades been fixated on the idea that clumps, or plaques, of beta-amyloid are the main factor driving the disease, and the new Lilly data bolster that hypothesis. But the session served as a reminder that breakthroughs like Ascherio’s can come from scientific backwaters, and that it would be a mistake not to support other worthy lines of inquiry. In the past, research into other explanations for Alzheimer’s — such as Ruth Itzhaki’s research on the role of viruses — has been stymied by the narrow focus on amyloid.

Itzhaki, a neuropathologist at the University of Manchester who has led much of the work linking HSV-1 and Alzheimer’s, believes it’s already clear the virus is a major trigger of the disease. That was something she suspected more than 30 years ago, in part because HSV-1 can cause damage and inflammation in the same parts of the brain affected by Alzheimer’s.

Another indirect hint, Itzhaki said during the panel, was that HSV-1 and Alzheimer’s are both common. Nearly half of people in the U.S. have been infected with the virus, and nearly 6 million Americans have Alzheimer’s, a figure experts expect to double by 2050.

So scientists examined the brain tissue of deceased donors who had Alzheimer’s as well as those who didn’t. They found viral DNA in a high proportion of the brains of Alzheimer’s patients, although it was also found in older adults without the disease. The association between Alzheimer’s and the presence of viral DNA only showed up in patients carrying APOE4, a genetic variant that increases a person’s risk of the disease.

That finding and others have caused Itzhaki to propose that reactivation of HSV-1, a virus that typically infects people early in life and lays dormant in nerve cells, can cause inflammation and damage and later trigger Alzheimer’s.

More recent work has found when human brain organoids, or “mini-brains,” are infected with HSV-1 in the lab, these small 3D balls of neural cells develop some characteristics of Alzheimer’s, including clumps of beta-amyloid.

In a 2021 review, Itzhaki characterized the evidence for the link between HSV-1 and Alzheimer’s as overwhelming — and the evidence against it as underwhelming.

“From our results, it looks as if 50% to 60% of people who get the disease are those for whom it’s caused by herpes simplex virus,” she said, adding that other microbial and non-microbial factors could account for the remainder of cases.

The virus research fascinates Ascherio. But the epidemiologist cautioned that the current evidence from Itzhaki and others is, in his view, preliminary, and that it’ll take much bigger and longer-term studies that track participants over time to draw a conclusive link.

“Alzheimer’s is a disease that has 20, 30 years of history behind it. We need to start from young, middle-aged adults, follow them in terms of their infection history, then determine what happens,” he said. “And we can do that.”

Ascherio’s own findings linking Epstein-Barr virus, or EBV, to multiple sclerosis came from sifting through a massive dataset: More than 62 million blood samples drawn from more than 10 million active- and reserve-duty military members. Researchers found that EBV infection increased a person’s likelihood of developing multiple sclerosis by more than 32-fold.

He noted that samples from the Department of Defense Serum Repository could help shed light on the connection between HSV-1 and Alzheimer’s, though researchers would probably also need to access data kept by the Department of Veterans Affairs given that Alzheimer’s patients are usually diagnosed late in life. Ascherio said he’s been working with the government to make these data links possible, which could allow scientists to ask a range of scientific questions.

His team’s widely cited MS paper hasn’t made it any easier for Ascherio to secure funding for future research, he said, but he is now looking into possible connections between viral and bacterial infection with amyotrophic lateral sclerosis, or ALS, another devastating neurological disease. He said progress on the project, in which he’s looking to access samples through the VA, has been slow in part because of bureaucratic red tape.

“It’s important people realize viruses and bacteria can cause chronic disease and not just acute infection,” Itzhaki said.

She and Ascherio agreed there’s growing evidence for this idea in certain cases, though it was once considered heretical in the Alzheimer’s world. Itzhaki’s 1991 study was rejected by nearly half a dozen journals before it was published by the Journal of Medical Virology.

Amyloid continues to dominate much of the field. Just hours before Ascherio and Itzhaki spoke, Lilly announced Phase 3 results showing that its beta amyloid-targeting antibody donanemab slowed the cognitive and functional decline of Alzheimer’s patients by 35%.

Itzhaki’s findings don’t argue against a role for amyloid, just not as the central driver in disease. Key evidence for or against her hypothesis could come from an ongoing clinical trial, expected to conclude around the end of this year, that is testing the effectiveness of the antiviral valacyclovir in treating adults with mild Alzheimer’s who also test positive for HSV-1.