Unusually high herpesvirus levels found in Alzheimer’s brain tissue

Mount Sinai researchers identify networks for developing new therapies to treat Alzheimer’s disease

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NEW YORK, NY—According to researchers from the Icahn School of Medicine at Mount Sinai, two strains of human herpesvirus—human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) —are found in the brains of people with Alzheimer’s disease at levels up to twice as high as in those without Alzheimer’s. Using evidence from postmortem brain tissue from the Mount Sinai Brain Bank, the research team also identified previously unknown gene networks that will both offer new testable hypotheses for understanding Alzheimer’s pathology, and reveal potential targets for new drugs. 
This is the first study to use a data-driven approach to study the impact of viruses on Alzheimer’s and to identify the role of HHV-6A and HHV-7 in the disease.  This is also the first evidence that integration of HHV genomes into human brain genomes may play a role in the etiology of Alzheimer’s. Results of the study, “Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus,” were published online in Neuron in June.
“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 of the Institute for Next Generation Healthcare at the 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 research team initially performed RNA sequencing on four brain regions in more than 600 samples of postmortem tissue from people with and without Alzheimer’s to quantify which genes were present in the brain, and whether any were associated with the onset and progression of Alzheimer’s. Through a variety of computational approaches, the team uncovered a complex network of unexpected associations, linking specific viruses with different aspects of Alzheimer’s biology. They examined the influence of each virus on specific genes and proteins in brain cells, and identified associations between specific viruses and amyloid plaques, neurofibrillary tangles, and clinical dementia severity.
To evaluate the robustness of their findings, the team incorporated a further 800 RNA sequencing samples collected by the Mayo Clinic and Rush Alzheimer’s Disease Center, observing a persistent increase of HHV-6A and HHV-7 abundance in samples from individuals with Alzheimer’s, thus replicating their main findings in two additional, independent, geographically dispersed cohorts.
Dudley noted that this study could potentially translate to the identification of virus, or virus-related, biomarkers that could improve patient risk stratification and diagnosis, as well as implying novel viral targets and biological pathways that could be addressed with new preventative and therapeutic drugs. As with any complex set of findings, they will need to be confirmed in additional patient cohorts, and further studies to specifically address a causal role for viruses are now being conducted by the research team.
“This is the most compelling evidence ever presented that points to a viral contribution to the cause or progression of Alzheimer’s,” said one of the study’s authors, Sam Gandy, MD, PhD, Professor of Neurology and Psychiatry and Director of the 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 has been enabled by the extensive molecular profiling of several large patient cohorts, generated in the course of the National Institute on Aging (NIA) Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD). Through the generation of this large, multi-omic resource, the team was able to perform their investigation of viral activity in Alzheimer’s in an entirely data-driven manner.  
According to a video about the research featuring Gandy and Dudley, “…what this study found was that viruses appear to be playing a role in the pathology of Alzheimer’s disease and viruses had been implicated in Alzheimer’s disease in the past, but more through population studies, through just sort of correlations, so no one really took it seriously,” Dudley notes. “And I think this was the first study where we used advanced genomic sequencing technologies directly from the affected brains of Alzheimer’s patients and were able to not only measure virus in these brains, but actually using computational techniques, sort of build out the network in which these viruses are operating and influencing known Alzheimer’s genes.”
Gandy continues, “When Alzheimer’s clusters in families, that tends to point to genes, and we often can find some of the genes that are playing a role in any particular family. What this [research] shows that’s different is that those genes might be turned on or turned off by viruses. It might be a combination of having both the gene and the exposure to the virus that makes someone have a disease. We’ve found that these HHV-6 and HHV-7 viral DNAs, these genomes, seem to regulate expression that we know cause risk for Alzheimer’s disease.”
“What this does is really strengthen this emerging theme that the innate immune system plays a role in Alzheimer’s, and why that gives us hope is that it’s going to reveal a whole set of new potential drug targets for Alzheimer’s and perhaps be able to borrow a lot of the tools and even drugs from immunology for Alzheimer’s disease,” concludes Dudley.

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