High abundance of human herpes viruses found in Alzheimer’s brains

Wayne Kuznar, for MDLinx | July 19, 2018

Patients with Alzheimer’s disease (AD) may have an abundance of human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) in their brains compared with those without AD, according to researchers from the Icahn School of Medicine at Mount Sinai, New York, NY, who published their results in Neuron.

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Postmortem examinations have revealed an increased presence of human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) in the brains of patients with Alzheimer’s disease.

This study represents the first evidence that integration of HHV genomes into human brain genomes may play a role in the etiology of AD.

“We examined four, large multi-omic datasets that included next-generation sequence data that enabled direct examination of viral sequences,” the investigators wrote. “We observed the presence of many viral species in the aging brain and linked multiple viral species with AD biology, including regulation of AD genetic risk networks, AD gene expression changes, and association with clinical dementia rating and neuropathology burden.”

Further, “the integrated findings of this study suggest that AD biology is impacted by a complex constellation of viral and host factors acting across different timescales and physiological systems.”

The researchers first performed RNA sequencing on four brain regions in more than 600 samples of postmortem tissue. Tissue was obtained from a cohort of AD and control brains from the Mount Sinai Brain Bank in order to quantify viral abundance in AD and assess the association between viral species and onset and progression of AD. A differential abundance of multiple viral species was found in the anterior prefrontal cortex (APFC) and the superior temporal gyrus (STG).

“The most consistent difference we saw was an AD-associated increase in the abundance of two closely related Roseoloviruses, HHV-6A and HHV-7, across the APFC and STG,” the researchers wrote.

Further, they identified an increased abundance across the APFC and STG regions of the HHV-6A U3/U4 genes and the HHV-7 direct repeat terminal gene, DR1. These findings were confirmed by RNA sequencing in additional independent cohorts.

Analysis of samples of the temporal cortex of individuals with AD, pathologic aging, and progressive supranuclear palsy (PSP) showed that “elevated HHV6-A and HHV-7 are not ubiquitous features of neurodegenerative disease, although HHV6-A may also be relevant to other diseases such as PSP.”

In an analysis to identify significant associations between virus level and viral gene level RNA abundance and AD-relevant traits, they identified several viral genes that significantly and positively associate with multiple AD traits, including the HHV-7 DR1 gene and HHV-6A unique region.

To determine whether these viral species represent a causal component of AD or are simply a passenger of a neurodegenerative process driven by other factors, whole exome sequencing data were integrated with RNA sequencing for each donor brain. They found significant overlap between the genetic basis for AD traits and the abundance of specific viral species and viral genomic features, supporting the hypothesis that viral activity plays a role in the development and progression of AD.

“This study represents a significant advancement in our understanding of the plausibility of the pathogen hypothesis of Alzheimer’s,” said the study’s senior author, Joel Dudley, PhD, director, Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai. “Our work identified specific biological networks that offer new testable hypotheses regarding the role of microbial defense and innate immune function in the pathophysiology of Alzheimer’s. If it becomes evident that specific viral species directly contribute to an individual’s risk of developing Alzheimer’s or their rate of progression once diagnosed, then this would offer a new conceptual framework for understanding the emergence and evolution of Alzheimer’s at individual, as well as population, levels.”

The hope is that the study translates to the identification of virus or virus-related biomarkers that could improve risk stratification and diagnosis of AD, as well as implying novel viral targets and biologic pathways that could be targeted with preventative and therapeutic drugs, he added.

“This is the most compelling evidence ever presented that points to a viral contribution to the cause or progression of Alzheimer’s,” said co-author, Sam Gandy, MD, PhD, professor of neurology and psychiatry and director, Center for Cognitive Health and NFL Neurological Care at Mount Sinai. “A similar situation arose recently in certain forms of Lou Gehrig’s disease. In those patients, viral proteins were discovered in the spinal fluid of some Lou Gehrig’s patients, and patients with positive viral protein tests in their spinal fluid showed benefit when treated with antiviral drugs.”

This study was funded by the National Institute on Aging, Cure PSP Foundation, Mayo Foundation, Michael J. Fox Foundation for Parkinsons Research, the Illinois Department of Public Health, and the Translational Genomics Research Institute. Philanthropic financial support was provided by Katherine Gehl.

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