A Common Virus May Play Role in Alzheimer’s Disease, Study Finds
Posted June 21, 2018 12:35 p.m. EDT
It has long been a controversial theory about Alzheimer’s disease, often dismissed by experts as a sketchy cul-de-sac off the beaten path from mainstream research.
But a new study by a team that includes prominent Alzheimer’s scientists who were previously skeptics of this theory may well change that. The research offers compelling evidence for the idea that viruses might be involved in Alzheimer’s, particularly two types of herpes that infect most people as infants and then lie dormant for years.
The study, published Thursday in the journal Neuron, found that viruses interact with genes linked to Alzheimer’s and may play a role in how Alzheimer’s develops and progresses.
The authors emphasized they did not find that these viruses cause Alzheimer’s. But their research, along with another soon-to-be-published study, suggests that viruses could kick-start an immune response that might increase the accumulation of amyloid, a protein in human brains which clumps into the telltale plaques of Alzheimer’s.
“These viruses are probably significant players in driving the immune system in Alzheimer’s,” said Joel Dudley, the study’s senior author and an associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai in New York. “I think they’re like gas on the flames of some pathology that may be immune-driven.”
If so, that could change the course of research and possibly lead to treatments and new ways of screening for the disease.
“This definitely brings up the potential role of infection or infectious particles in the pathology of Alzheimer’s,” said Dr. John Morris, director of the Knight Alzheimer’s Disease Research Center at Washington University School of Medicine in St. Louis.
Morris, who was not involved in the research, said it provided the strongest evidence to date for a viral role. The study analyzed samples from nearly 950 human brains in four different brain banks and found links to the genetic, molecular and clinical symptoms of Alzheimer’s.
“It’s a very complex disease, and the answer’s not going to be one thing,” he said. “If viruses are a part of that, we definitely need to take a look at it.”
The virus theory is far from being accepted by most Alzheimer’s experts. Some raise the chicken-or-egg question: Could viruses found in greater amounts in Alzheimer’s brains be consequences of the disease or even, as Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease in San Francisco said, “innocent bystanders”?
Mucke called the new study “impressive and very well designed.” But, he noted, “there have been many speculations and even outright claims that infections contribute to the development of Alzheimer’s disease.”
“None of them has held up after rigorous cause-effect evaluations,” he added.
Still, the new findings will be bolstered by another upcoming study in Neuron, led by Rudolph Tanzi and Robert Moir, neuroscientistss at Massachusetts General Hospital and Harvard, who have broken ground on the virus idea for years.
Their new experiments, performed in mice and three-dimensional brain cells in a dish, found that the same herpes species ignited a protective reaction in amyloid, a protein present in all human brains. Tanzi describes this as “seeding” the amyloid, causing it to ensnare the virus in fibrous nets that form plaques.
In this way, he said, viruses and other microbes are the “prequel” to the prevailing theory that Alzheimer’s is caused by amyloid accumulation the brain cannot clear out.
For the study published Thursday, Dudley, who described himself as a “big data guy,” not an Alzheimer’s expert, was asked by the National Institutes of Health to help generate new Alzheimer’s ideas by analyzing information from a consortium involving many brain banks and researchers.
Dudley was interested in whether existing drugs could be repurposed to treat Alzheimer’s, which has so far resisted all drugs tested in hundreds of clinical trials. To start, he and colleagues created computer models mapping the molecular and genetic networks disrupted as Alzheimer’s progresses.
What the scientists found surprised them. Genes that were active in Alzheimer’s pathology also turned out to be active in fighting viruses.
“I went looking for drugs, and all I found were these stupid viruses,” Dudley joked.
Then the researchers searched in about 2,000 samples from 944 brains of people who had died — some with Alzheimer’s, some with other types of neurological problems, and some without cognitive impairment. The idea was to see if any viral gene sequences were more abundant in Alzheimer’s brains.
Although some previous Alzheimer’s studies had focused on herpes, “we had no horse in the race and said, ‘We’re going to look across all viral genes known to man,'” Dudley said.
Out of 515 viruses, Alzheimer’s brains consistently had more of two herpes species: 6A and 7. These belong to a family of roseoloviruses that affect almost every baby, sometimes causing a pinkish rash and fever. They then go dormant, but can later get reactivated for various reasons, including illness or stress.
These herpes species have the ability to enter brain cells. And, said Dudley, “The viruses have a direct sort of push-pull with lots of known Alzheimer’s genes.”
In fact, people with the gene most known to increase the risk of getting Alzheimer’s, ApoE4, had even more of herpes 6A, said Ben Readhead, the study’s first author, affiliated with the Icahn School of Medicine and the Arizona State University-Banner Neurodegenerative Disease Research Center.
And genes that seemed to make tissues more susceptible to harm from the herpesviruses were expressed most strongly in two brain areas that are especially damaged in Alzheimer’s, Dudley said.
But herpes may not be the only infection that triggers the brain’s immune response, Tanzi said. Bacteria, parasites and other microbes might, too.
“It could lead to new therapeutic strategies down the road,” said Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix and one of several Alzheimer’s experts and longtime virus-theory skeptics who were co-authors on the study.
For example, experts said, it might make sense to develop vaccines or drugs to pre-empt infections most linked to Alzheimer’s and to screen people for genes that increase vulnerability to those infections. The goal, said Reiman, is to “find better ways to understand and treat the disease — including ways that may defy preconceived notions.” Dudley said he is unsure whether many mainstream Alzheimer’s researchers will endorse the virus idea anytime soon.
“It’s very unpopular,” he said. “I’m sure there’s a lot of people who are secretly unhappy about it.”
Still, he said, Alzheimer’s researchers “come up to me at conferences and say in hushed tones, ‘Oh, I also have a data set that shows viruses, but I’m afraid to publish it.'”