New study supports long-dismissed idea: Herpes viruses could play role in Alzheimer’s

The most detailed molecular analysis of hundreds of brains from people who died with Alzheimer’s disease lends support to an idea that has struggled for funding, been rejected by top journals, and met with ridicule from the Alzheimer’s orthodoxy: that viruses, bacteria, or fungi in the brain play a role in the devastating neurodegenerative disease.

If pathogens either initiate or accelerate Alzheimer’s, then classes of drugs that have never been considered for the disease should be in play. The new study, published Thursday in Neuron, “should bring forward new therapeutic targets and enable the field to predict which drugs out there may be useful,” such as antimicrobials, said Suzana Petanceska of the National Institute on Aging.

A second study, scheduled for publication next month, also points a finger at pathogens. “I wouldn’t say the new studies provide the smoking gun,” said neurobiologist George Perry of the University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease. “But I do think the evidence is continuing to build that infectious agents play a role in this disease.”

During the 14 months that the two studies have been stuck in publication limbo, experimental Alzheimer’s drugs based on the quarter-century-old “amyloid cascade hypothesis” have been flaming out, each more spectacularly than before. (The hypothesis says that production of an aberrant protein called amyloid-beta creates sticky plaques that destroy brain synapses and neurons.) This year alone has brought the demise of the Eli Lilly/AstraZeneca drug lanabecestat; Lilly’s solanezumab; and Merck’s verubecestat. That brings the number of effective Alzheimer’s treatments based on the amyloid cascade hypothesis to … zero, making the need for new ideas more urgent than ever.

For the Neuron paper, scientists led by Joel Dudley, an expert in genomics and bioinformatics at the Icahn School of Medicine at Mount Sinai, examined 622 brains from people who died with Alzheimer’s — the largest number ever analyzed in this detail — and 322 healthy brains. He and his colleagues basically went fishing, looking for genes whose activity changes with Alzheimer’s. While doing that, “we were surprised to see evidence of herpes viruses” in the brains, said co-author Dr. Sam Gandy of Mount Sinai.

They then ran what’s called an unbiased scan, looking not for particular viruses but asking the open-ended question: What non-human genetic material is in the brains?

Using several forms of molecular profiling, from DNA sequencing to proteomics, they got a clear answer: “all sorts, and lots of it.” Especially in brain regions where vast numbers of neurons die in Alzheimer’s, the scientists found that three strains of herpes virus — human herpes virus 6A, 6B, and 7 — were prevalent, reaching levels up to twice that in healthy brains.

In four regions that are ravaged by Alzheimer’s — including the hippocampus, which plays a key role in memory — about one-quarter of the Alzheimer’s brains had evidence of HHV-6A, 22 percent had HHV-6B, and 29 percent had HHV-7. “The fraction of samples that had at least one of these in at least one brain region was substantially higher,” said co-author Ben Readhead of Arizona State University.

“This is the first study to provide strong evidence based on unbiased approaches and large data sets that lends support” to the idea that pathogens are involved in Alzheimer’s, said Dr. Richard Hodes, director of the National Institute on Aging.

Merely finding herpes virus, however, falls well short of demonstrating that it or other microbes cause Alzheimer’s. That idea has been kicking around since at least the 1950s but has never overcome a key objection: degenerating brains might just be more inviting to pathogens than healthy brains. In that case, the pathogens would be opportunistic, not causal, sneaking across the blood-brain barrier and taking up residence only after Alzheimer’s has developed.

None of the earlier claims that infectious agents spur the development of Alzheimer’s “has held up after rigorous evaluation across multiple laboratories,” said Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease. Moreover, he added, previous studies showed only an association, not causation.

But Dudley and his colleagues took a step toward showing causation, and therefore going beyond previous research, by finding that viruses had also slipped their genes into the DNA of cells in the Alzheimer’s brains. The viral genes seem to influence the expression, or activity, of genes associated with Alzheimer’s, including such famous ones as presenilin-1, BACE1, and several that direct the production of amyloid beta precursor proteins.

The viral genes, Dudley said, seem to be activating proteins that in turn activate the Alzheimer’s genes, perhaps “acting as an environmental trigger to some of the genetic risk markers.”

Another hint of causation: “Viruses are overrepresented in the worst cases of Alzheimer’s, and seem to track the severity of disease,” Gandy said.

Herpes viruses are extremely common. HHV-6 is found “in pretty much everybody over 2,” said Robert Moir of Massachusetts General Hospital, co-author of a paper on HHV6 and Alzheimer’s that will appear next month in Neuron. (Like Dudley’s, it took more than a year to be published, including time lost when the journal Cell initially accepted it for review and then rejected it.) But clearly not everyone who carries herpes virus (which often stays dormant for years ) develops Alzheimer’s.

That may be because the viruses don’t usually cross the blood-brain barrier (though there is some evidence they can get in from the nose via the olfactory nerve). But in some people, for unknown reasons, they might.

What this all might mean for Alzheimer’s treatment isn’t clear. The new paper “raises a lot of questions that we should be looking at,” said Heather Snyder of the Alzheimer’s Association, “including [Alzheimer’s-causing] mechanisms involving the immune system.” At minimum, said neuroscientist Miroslaw Mackiewicz of the National Institute on Aging, the study should make scientists consider “drug targets that are above and beyond” those involved in producing amyloid-beta.

There’s also a simple treatment idea, suggested by a little-noticed study published in April. Scientists in Taiwan followed 8,362 people who were diagnosed with herpes infections in 2000, and 25,086 people without the infections. The herpes-infected group was 2.6 times as likely to develop dementia. But in people treated with antiviral drugs, that risk was reduced by 90 percent.