Herpesviruses 6A and 7 (HHV-6A and HHV-7) — two of the nine known members of the Herpesviridae family that infect humans — are found in the brains of patients with Alzheimer’s disease at levels up to twice as high as in those without Alzheimer’s, according to a new study appearing in the journal Neuron. This is the first evidence that integration of herpesvirus genomes into human brain genomes may play a role in the etiology of Alzheimer’s disease.
An electron micrograph of human herpesvirus-6 particles. Image credit: Bernard Kramarsky / Laboratory Of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services.
This new study, led by Dr. Joel Dudley of the Icahn School of Medicine at Mount Sinai, is the first to use a data-driven approach to investigate the impact of viruses on Alzheimer’s and to identify the role of HHV-6A and HHV-7 in the disease.
“Our study represents a significant advancement in our understanding of the plausibility of the pathogen hypothesis of Alzheimer’s,” Dr. Dudley said.
“We 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.”
In the study, Dr. Dudley and co-authors 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 researchers 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, 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.
“Our 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,” Dr. Dudley said.
“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 Professor Sam Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center and chairman emeritus of the National Medical and Scientific Advisory Council of the Alzheimer’s Association.
“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.”
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Ben Readhead et al. Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron, published online June 21, 2018; doi: 10.1016/j.neuron.2018.05.023
