A new finding that even took the study’s authors by surprise lends support to the controversial idea that microbes play a role in Alzheimer’s disease. The research, published June 21 in Neuron, found convincing signs that certain types of herpes virus may promote the complex process that leads to the disease that afflicts some 5.7 million Americans. The study points to the viruses as possible accomplices that drive disease progression but does not suggest that Alzheimer’s may begin after they are transmitted through casual contact.

The research community has been seeking new insights into the pathology of Alzheimer’s because decades of research and hundreds of failed clinical trials have only resulted in disagreements about its underlying biology—and no new treatments have emerged to modify the course of the memory-robbing disease. The long-standing amyloid hypothesis posits that symptoms are triggered by the buildup of amyloid beta brain plaques, but trials of drugs that attempt to clear these plaques have so far flopped. Skeptical researchers have hunted for other explanations, and some have zeroed in on microbes. In March 2016 in the Journal of Alzheimer’s Disease, 33 international scientists penned an editorial urging the research community to seriously consider the idea that pathogens could be involved.

Joel Dudley, a geneticist and genomic scientist at the Icahn School of Medicine at Mount Sinai and senior author of the new paper, had not intended to investigate this theory when his lab began working on the newly published study in 2013. The plan he had made with colleagues was to identify possible new Alzheimer’s drug targets by looking at the molecular changes in the brain that occur during the disease.

Thanks to a new NIH-led public-private partnership called the Accelerating Medicines Partnership – Alzheimer’s Disease (AMP-AD), the team had access to data from 876 brains—some healthy and some with early- or late-stage Alzheimer’s. They used DNA and RNA sequencing to parse out genetic differences between the groups as well as differences in how inherited genes were expressed or made into RNA. That’s when they started getting strange results. “The algorithms kept returning this pattern for viral biology,” Dudley says.

The team found more viral DNA in Alzheimer’s brains compared with healthy brains—specifically, high levels of DNA from human herpesvirus 6A (HHV-6A). RNA of both HHV-6A and HHV-7 were also higher in the Alzheimer’s brains than in healthy brains, and viral RNA levels tracked with the severity of clinical symptoms. HHV-6A is a usually symptom-less virus that infects people later in life. HHV-7 infects more than 80 percent of infants, often causing a rash.

They then tried to determine whether viruses are involved in the progression to Alzheimer’s or whether they are, instead, bystanders or somehow consequences of the disease; it might have been the case, for instance, that people with Alzheimer’s were more susceptible to viral infections. To probe this question, the team created the equivalent of a biological social network to probe how various molecular and genetic signals were interacting with each other. They found that viral genes were influencing other known Alzheimer’s genes and molecules—evidence that the viruses are directing at least part of the disease process. “It was really striking,” says Sam Gandy, a co-author who is a Mount Sinai neurologist and amyloid expert. The viruses “seemed to be talking to some of the networks that contained some of the familiar Alzheimer’s-related genes.” The researchers also identified a microRNA— a short molecule that typically switches genes off—that is suppressed by the HHV-6A virus in Alzheimer’s brains. When they later bred mice deficient in this microRNA, they found that the rodents developed larger and more abundant amyloid plaques in their brains than did mice with normal microRNA levels.

The Alzheimer’s community remains cautious about the findings. “Possible roles for microbes and viruses in Alzheimer's disease have been suggested and studied for decades, but previous research has not explained how they may be connected. This is the first study to provide evidence based on multiple, large data sets that lends support to this idea,” says Keith Fargo, director of scientific programs and outreach at the Alzheimer’s Association. But “more research is needed to discover exactly what roles, if any, they play. The new findings do not prove that the viruses cause the onset or contribute to the progression of Alzheimer's disease.”

Gandy and Dudley stress that they don’t believe Alzheimer’s is an infectious disease that can be transmitted like the common cold. “What I believe is that in genetically or physiological susceptible individuals, the virus is acting as an agonist of the disease,” Dudley says—a number of processes likely participate, with viruses being just one piece of the puzzle. Most people have antibodies that indicate they have been infected with HHV-7, for instance, yet few develop Alzheimer’s. Recent research has also implicated viruses in the development of Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Yet even if viruses only abet disease progress, that realization could open the door to better ways to diagnose and treat Alzheimer’s. It might be possible to use certain biological markers of the viruses to identify high-risk individuals. Antiviral drugs could also be explored as a potential preventive treatment. In February 2018, Taiwanese researchers reported that individuals infected with herpes simplex virus 1 (HSV-1), the virus that causes cold sores, were 90 percent less likely to develop senile dementia than infected people who weren’t treated if they received treatment with antiviral drugs.

HSV-1 is a different virus from HHV-6A and HHV-7, but Dudley’s team did also find that Alzheimer’s brains had higher than normal levels of genetic material associated with HSV-1. Many other papers have linked HSV-1 with Alzheimer’s and studies have also implicated bacteria as culprits, including pneumonia-causing bacteria and the spirochetes that cause Lyme disease.

A series of studies led by Massachusetts General Hospital neurologist Robert Moir and colleagues suggests a possible theory to bind these disparate pathogen findings together: Beta amyloid proteins may accumulate in the brain as part of an immune response against injury or invading pathogens. In a paper published online on June 21st, also in Neuron, Moir and colleagues reported that amyloid beta peptides bind to and entrap HSV-1 and HHV-6, thereby helping to protect against infection. Mice infected with these herpes viruses quickly accumulate beta amyloid plaques, too. Their theory posits that when enough beta amyloid plaques build up during an infection, they then trigger inflammation and other unhelpful responses, such as the creation of tau tangles that kill neurons. The plaques also alert brain immune cells called microglia to the fact that something is wrong; these cells launch an immune cascade that kills even more neurons. The end result of this process— which began with a seemingly protective response to microbial invasion—could be Alzheimer’s.

Strengthening the evidence for this controversial idea will be difficult. Dudley has met researchers at conferences who have confided in him that they have also collected data implicating pathogens in the disease but that they have been too scared to publish—for fear that they will be ostracized by the Alzheimer’s community. Ruth Itzhaki, a neurobiologist at the University of Manchester in the U.K., who has led many of the studies linking HSV-1 with Alzheimer’s, says she has suffered “derision and vituperative hostility” for pursuing this line of inquiry.

But Dudley is willing to accept the risks and push forward. “Look, my life would be easier, too, if we hadn’t found these viruses,” he says. “But the data are the data.”