Herpesvirus May Drive Development, Progression of Alzheimer's

Batya Swift Yasgur, MA, LSW

June 22, 2018

The human herpesvirus (HHV) may play a role in the development and progression of Alzheimer's disease (AD), new research suggests.

In a potentially game-changing study, investigators analyzed large data sets of postmortem brain tissue and found that for patients with AD, levels of HHV-6A and HHV-7 were twice as high as in persons without AD.

Moreover, there were multiple points of overlap between virus-host interactions and the genes associated with AD risk.

"We were looking for genes that changed during the progression of AD, especially ones that changed most dramatically, and were surprised to find that the genes we found seemed related to herpesvirus," co–lead investigator and co–senior author Samuel Gandy, MD, PhD, associate director of the Mount Sinai Alzheimer's Disease Research Center and professor of neurology and psychiatry at the Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.

"If we continue to find evidence that these viruses are overrepresented in AD, there's a reasonable chance that antiviral agents will inhibit the production of these herpesvirus strains, and a clinical trial of antivirals can be initiated in those patients," he said.

The study was published online June 21 in Neuron.

Seeking Novel Evidence

"Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of AD, although definitive evidence has not been presented," the authors write.

The researchers set out to present "novel evidence" linking the activity of viruses to AD by constructing "multiscale networks" of late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathologic data across four brain regions from human postmortem tissue.

They started by examining transcriptomes from brain regions that undergo the earliest changes and most profound neuronal loss in AD (the entorhinal cortex [EC] and hippocampus [HIP]) so as to understand the "more dramatic changes seen in later stages of AD."

They drew on data generated from the National Institutes of Health–sponsored Accelerated Medicine Partnership for Alzheimer's Disease and used whole-exome DNA sequencing to derive detailed information about each person's inherited genes. They used RNA sequencing to derive detailed information about the genes that were expressed differently in donors with and those without AD.

Laser-captured neuronal gene expression data were used to construct probabilistic causal networks that represented preclinical AD.

In addition, the researchers utilized clinical assessments performed before the death of study participants to understand the trajectory of cognitive decline. Postmortem neuropathologic assessments were used to determine the severity of amyloid plaques and tangles.

"Surprising, Perplexing"

Differential network analysis revealed that the genes that regulate network drivers were "strongly enriched" for a shared set of C2H2 zinc finger transcription factor (C2H2-TF) binding motifs and G-quadruplex (G4) sequences, "suggesting a potential role for virus-mediated activities in AD," the authors write.

The disturbances in G4 and C2H2-TF regulation in preclinical AD samples prompted the next stage of the research — evaluation of the role of viral activity in the development and progression of clinical AD.

The initial research used samples provided by the Translational Genomics Research Institute, Phoenix, Arizona. Further research was performed at the Mount Sinai Brain Bank, where the roseola viruses HHV-6A and HHV-7 were found to be more abundant in the superior temporal gyrus and anterior prefrontal cortex (APFC) in persons who had had AD in comparison with healthy control persons.

"We were surprised and perplexed" and "confirmed the observation [of the abundance of virus] in other brain banks to be sure it was correct and not an artifact that had somehow gotten into our brain bank," said Gandy.

The additional independent consortiums were derived from the Religious Orders Study and consisted of 300 samples from the dorsolateral prefrontal cortex (DLPFC) of individuals with AD and healthy control persons; the Rush Memory and Aging Project, consisting of 298 samples from the DLPFC of individuals with AD and from healthy control persons; and the Mayo Temporal Cortex (MAYO TCX), consisting of 278 samples from the temporal cortex of people with AD, people with other neurologic illnesses, and healthy control persons.

The main finding was a "consistently increased abundance" of HHV-6A and HHV-7.

Unique to AD

Further examination of these viral perturbations was conducted through analysis of four large, multiomic data sets that included next-generation sequencing data that enabled direct examination of viral sequences.

Abundance of viral RNA was found to be associated with AD dementia and neuropathologic traits. A number of viral genes were significantly associated (false discovery rate <.01) with multiple AD traits, including the HHV-7 DR1 gene and the HHV-6A gene.

The DNA variants that were associated with viral abundance were also associated with AD status and clinical dementia.

A comparison of samples within the MAYO TX cohort taken from individuals who did not have neuropathologic features of AD led the researchers to conclude that elevations in the levels of HHV-6A and HHV-7 are "not ubiquitous features of neurodegeneration."

The authors propose several potential mechanisms for the effect of the virus on AD development — for example, causal inference testing suggested that the HHV-6A virus and the HHV-6A U3/U4 gene mediated neuronal loss.

The virus was also found to perturb the transcription factor regulatory network.

"When you look at the viral genes in the setting of the network they're connected to, they often regulate the expression of genes we think are related to AD," said Gandy.

Response to Viral Insult?

AD may be the brain's response to viral insult, with production of amyloid beta — a hallmark of AD neuropathology — being a component of that response.

The researchers raised the question of whether these viral strains are "opportunistic passengers" of a "multidecade neurodegenerative process" or whether their relationship to AD is causal.

In consideration of previous research, they concluded that their "integrated findings" suggest that "AD biology is impacted by a complex constellation of viral and host factors acting across different time scales and physiological systems."

The study provides "the most compelling evidence to date supporting a viral contribution to the cause and progression of AD," Gandy commented.

"Provocative" Findings

Commenting on the report for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer's Association, who was not involved with the research, called it an "interesting" study by a "really excellent group of people."

The study "raises some provocative findings and provocative hypotheses, but I think they are still hypotheses at this point," he cautioned.

"It's important for the public to understand that this does not present any kind of proof that viruses are involved in a causative way in AD, although it does raise that possibility," he said.

He expressed concern that the public might think that, because the study hypothesizes a role for viruses, AD might be contagious. "We haven't seen any kind of evidence of this at all," he emphasized.

He added that "it is not clear — including after this paper — whether there is some type of causative connection or whether AD lends the brain to be more susceptible to infection with viruses," so clinical implications would be "very premature."

However, "what this paper does is to lay a stake in the ground for other researchers regarding something we need to pay attention to, understand what this relationship is, and what the direction of causality is — if any," he said.

Gandy acknowledged that further research is necessary.

"The next step is to see if we can find the herpesvirus in the body fluid, blood, and spinal fluid of living patients, and then we would definitely think about intervening once we find a way of identifying which patients are more likely to have [HHV] 6 or 7."

Details regarding funding for the studies, researchers, and institutions can be found in the original article. The authors and Dr Fargo have disclosed no relevant financial relationships.

Neuron. Published online June 21, 2018. Full text

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