First-of-its-kind research by ASU, Banner, Mount Sinai and others suggests species of herpesvirus contribute to development of disorder
Of the major illnesses facing humanity, Alzheimer’s disease (AD) remains among the most pitiless and confounding. More than a century after its discovery, no effective prevention or treatment exists for this progressive deterioration of brain tissue, memory and identity. With more people living to older ages, there is a growing need to clarify Alzheimer’s disease risk factors and disease mechanisms and use this information to find new ways in which to treat and prevent this terrible disorder.
A first-of-its kind study implicates another culprit in the path to Alzheimer’s disease: the presence of viruses in the brain.
In research appearing in the advance online edition of the journal Neuron, scientists at the Arizona State University-Banner Neurodegenerative Disease Research Center (NDRC) and their colleagues at the Icahn School of Medicine at Mount Sinai used large data sets from clinically and neuropathologically characterized brain donors and sophisticated “big data” analysis tools to make sense of both the genes that are inherited and those that are preferentially turned on or off in the brains of persons with Alzheimer’s disease. They provide multiple lines of evidence to suggest that certain species of herpesviruses contribute to the development of this disorder.
The new work brings science a step closer to clarifying the mechanisms by which infectious agents may play important roles in the disease. To achieve this, the team capitalized on DNA and RNA sequencing data from 622 brain donors with the clinical and neuropathological features of Alzheimer’s disease and 322 brain donors without the disease — data generated from the National Institutes of Health-sponsored Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD).
The “whole exome” DNA sequencing was used to provide detailed information about each person’s inherited genes. RNA sequencing from several brain regions was used to provide detailed information about the genes that are expressed differently in donors with and without the disease.
Clinical assessments performed before the research participants died provided detailed information about their trajectory of cognitive decline, and neuropathological assessments performed after they died provided relevant neuropathological information, including the severity of amyloid plaques and tangles, the cardinal features of Alzheimer’s disease. Sophisticated computational tools were used to develop a kind of grand unified picture of the viral-AD nexus.
Big challenges, big data
Big data-driven analyses offer a particularly powerful approach for exploring diseases like Alzheimer’s, which involve many interdependent variables acting in concert in profoundly complex systems. In the current study, researchers explore viral presence in six key brain regions known to be highly vulnerable to the ravages of AD. (It is now accepted that damaging effects to these areas often precede clinical diagnosis of the disease by several decades.)
The study identifies high levels of human herpesvirus (HHV) 6A and 7 in brain samples showing signs of AD neuropathology, compared with the lower levels found in normal brains. Further, through the careful comparison of large data sets of viral RNA and DNA with networks of human genes associated with AD and signposts of neuropathology, the study offers the first hints of the viral mechanisms that could trigger or exacerbate the disease.
The findings, originally hinted at from samples provided by Translational Genomics (TGen) in Phoenix, were confirmed in the Mount Sinai Brain Bank, and then replicated in samples from the Mayo Clinic Brain Bank, Rush Alzheimer’s Disease Center, and the Banner-Sun Health Research Institute’s Brain and Body Donation Program.
According to Ben Readhead, lead author of the new study, the researchers’ general goal was to discover disease mechanisms, including those that could be targeted by repurposed or investigational drug therapies.
“We didn’t go looking for viruses, but viruses sort of screamed out at us,” Readhead said.