



Results from a major analysis of genetic and molecular networks in the brains of Alzheimer’s disease (AD) patients have suggested a role for two human herpesvirus species. The study, headed by a team at the Icahn School of Medicine at Mount Sinai, found increased levels of the two Roseoloviruses, human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV7), interacting with gene networks in areas of the brain that are known to be affected in AD. While the researchers are not claiming that the viruses play a causal role in AD progression, they do hint that viral mechanisms could exacerbate or even trigger the disease.

“Previous studies of viruses and Alzheimer's have always been very indirect and correlative,” states Joel Dudley, Ph.D., associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai and associate research professor at the Arizona State University-Banner Neurodegenerative Disease Research Center (NDRC). “But we were able to perform a more sophisticated computational analysis using multiple levels of genomic information measured directly from affected brain tissue. This analysis allowed us to identify how the viruses are directly interacting with or coregulating known Alzheimer's genes. I don't think we can answer whether herpesviruses are a primary cause of AD. But what's clear is that they're perturbing and participating in networks that directly underlie Alzheimer's pathophysiology.”

The Icahn School of Medicine team and collaborators report their findings today in Neuron, in a paper entitled “Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks for Human Herpesvirus.”

The idea that microbes and viruses may somehow contribute to the onset and progression of AD has been mooted for at last 60 years, but studies have yet to generate definitive evidence, the authors explain. “Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve.”

For the new study, which was broadly designed to map and compare genetic, transcriptional, and protein networks underlying AD, the team analyzed whole exome DNA and RNA sequencing data from 622 brain donors with early- and later-stage clinical and neuropathological features of AD, and another 322 brains from donors without the disease, generated through the National Institutes of Health (NIH)-sponsored Accelerated Medicines Partnership for Alzheimer’s Disease (AMP-AD). Each patient had undergone clinical evaluation to follow the course of their disease before death and neuropathological evaluation to evaluate factors, including the degree of amyloid plaque formation. The initial aim of the study was to uncover disease mechanisms and potentially identify targets for new drugs, or for repurposing existing drugs. “Our strategy began by examining transcriptomes from brain regions that undergo the earliest changes in AD with the goal of identifying novel biology that could offer a frame for understanding the more dramatic changes seen in later stages of AD,” the authors write.

Initial investigations of viral sequences were carried out using data from the Mount Sinai Brain Bank. Observations were then verified using datasets from the Religious Orders Study, the Memory and Aging Project, and the Mayo Clinic Brain Bank. Incorporating data from the Emory Alzheimer’s Disease Research Center provided insight into viral impact on proteins. “We evaluated the set of genes causally regulated by each virus, against a set of known AD-associated genes, including risk genes for early- and late-onset AD, as well as AD-associated traits, such as beta-amyloid plaque density, rate of disease progression, neurofibrillary tangle density) from multiple human genetics disease resources.”

Using computational tools to analyze these large datasets, the researchers were able to generate a picture of the genetic, transcriptional, and molecular networks that underpin AD development and progression and how viruses are potentially involved. Their results found a number of common viruses in normal aging brains, but more specifically identified increased levels of HH-6A and HH-7 in AD brains, a finding that was subsequently validated in the additional patient cohorts.

“We found prominent roles for Roseoloviruses HHV-6A and HHV-7, both implicated across multiple domains, and 3 independent cohorts,” the team writes. Comparisons between AD and other neuropathological controls, enabled through inclusion of one particular dataset, suggested that “HHV-6A and HHV-7 are not ubiquitous features of neuropathology and appear at least partially specific to AD,” the researchers comment. The data suggested that viruses directly interact with known AD risk genes. “HHV-6A stood out as a notable,” they state, and exhibited a significant overlap between the set of host genes it collectively induced across all tissues and AD-associated genes. “This includes several regulators of APP [amyloid precursor protein] processing and AD-risk-associated genes.” The constructed virus–host protein networks also suggested that herpesvirus interaction perturbed cell nucleotide pools, tRNA synthesis, and protein translation, “which suggested a picture of virally induced dysregulation of nucleotide pool metabolism, especially purine bases, consistent with several metabolomics studies in AD.”

“We didn’t go looking for viruses, but viruses sort of screamed at us,” states lead author Ben Redhead, assistant research professor at the NDRC. “We were able to use a range of network biology approaches to tease apart how these viruses may be interacting with human genes we know are relevant to AD…a number of viruses looked interesting. We saw a key virus, HHV-6A, regulating the expression of quite a few AD risk genes and genes known to regulate the processing of amyloid, a key ingredient in AD neuropathology.”

The networks described suggest that the characteristic features of AD may arise as collateral damage that is caused in response to a viral assault. This concept posits that the brain reacts to a viral infection by engulfing the viruses with amyloid beta (Aβ), to prevent them from binding with host cell surfaces.

The researchers were particularly interested in the microRNA (miRNA) miR-155, which has previously been linked with neuropathologic features of AD. Their data analyses and subsequent studies in experimental mice found that the HHV-6A virus effectively suppressed miR-155, leading to altered levels of Aβ and amyloid plaque density in vivo. “Collectively, these findings support the role of miR-155 as a key node in host response to AD-relevant viral perturbation, and as a potential mediator of neuronal loss,” they state. “This is is also consistent with the contribution of viral perturbation in driving the preclinical AD transcriptional phenotype, given that our prioritization of miR-155 was informed by findings in the preclinical AD networks.”

Although the hypothesis that viruses play a part in brain disease isn't new, “this is the first study to provide strong evidence based on unbiased approaches and large datasets that lends support to this line of inquiry,” comments NIA director Richard J. Hodes, M.D. “This research reinforces the complexity of AD, creates opportunities to explore Alzheimer's more thoroughly, and highlights the importance of sharing data freely and widely with the research community.”

“This study illustrates the promise of leveraging human brain samples, emerging big data analysis methods, converging findings from experimental models, and intensely collaborative approaches in the scientific understanding of AD and the discovery of new treatments,” adds study co-author Eric Reiman, M.D., executive director of the Banner Alzheimer's Institute and University Professor of Neuroscience at Arizona State University. “We are excited about the chance to capitalize on this approach to help in the scientific understanding, treatment, and prevention of Alzheimer's and other neurodegenerative diseases.”



























