In a large-scale analysis, researchers use data from three different brain banks to suggest that human herpesviruses are more abundant in the brains of Alzheimer's patients and may play a role in regulatory genetic networks that are believed to lead to the disease. This work lends support to the controversial hypothesis that viruses are involved in Alzheimer's disease and offers potential new paths for treatment.

The quest to understand what causes Alzheimer's disease — and to treat it — is complicated by the disease's long, slow progression and the difficulty of collecting brain tissue samples. But in a large-scale analysis published in the journal Neuron, researchers use data from three different brain banks to suggest that human herpesviruses are more abundant in the brains of Alzheimer's patients and may play a role in regulatory genetic networks that are believed to lead to the disease. This work lends support to the controversial hypothesis that viruses are involved in Alzheimer's disease and offers potential new paths for treatment.

The researchers analyzed data from three major brain banks courtesy of the National Institutes of Health's Accelerating Medicines Partnership — Alzheimer's Disease (AMP-AD) consortium, which allowed them to look at raw genomic data for large numbers of Alzheimer's patients in different cohorts. They constructed, mapped, and compared regulatory gene networks in areas of the brain known to be affected by Alzheimer's on multiple levels, looking at DNA, RNA, and proteins.

"This kind of analysis was only possible because the consortium had coordinated for all of these other groups to put their sequencing data in the AMP-AD Knowledge Portal in a pre-competitive environment that let us very quickly replicate our work across all these different cohorts. We needed access to sequences that are usually discarded in the course of studying the human genome. We needed to search for sequences from hundreds of different viruses, so having access to that raw, unprocessed data was absolutely key," says first author Ben Readhead.

They found that human herpesvirus DNA and RNA were more abundant in the brains of those diagnosed postmortems with Alzheimer's disease and that abundance correlated with clinical dementia scores. And the two viruses they found to be most strongly associated with Alzheimer's, HHV-6A and HHV-7, were not as abundant in the brains of those with other neurodegenerative disorders.

When they constructed networks that modeled how the viral genes and human genes interacted, they were able to show that the viral genes were regulating and being regulated by the human genes — and that genes associated with increased Alzheimer's risk were impacted.

The researchers believe that their findings align with other current research in the Alzheimer's field on the role of innate immunity in the disease, particularly recent findings that beta-amyloid protein — the culprit behind the plaques that build up in the Alzheimer's-affected brain — may accumulate as part of a defense against infections. In their study, they found that herpesviruses were involved in networks that regulate amyloid precursor proteins.

This is especially true because HHV-6A and HHV-7 are extremely common and often latent or asymptomatic: in North America, almost 90% of children have one of these viruses circulating in their blood by the time they're a few years old. "There are still a lot of unanswered questions around how we go from being able to detect it circulating in someone's blood to knowing whether it's active in a state that might be relevant to Alzheimer's disease," says Readhead.

"All these Alzheimer's brains in these separate, major brain banks have previously unsuspected substantial populations of herpesvirus genomes and that deserves an explanation wherever it falls in the pathogenesis. It doesn't deserve to just be brushed away," says Gandy.