New findings published in Neuron1 add to a growing body of evidence that suggests a role for viral species, particularly human herpesvirus (HHV), in the biology of Alzheimer disease (AD). While the findings are not causative, they do suggest an interaction between viral DNA sequences and the molecular, genetic, and clinical characteristics of AD.
“The hypothesis that viruses play a part in brain disease is not new, but this is the first study to provide strong evidence based on unbiased approaches and large data sets that lends support to this line of inquiry,” National Institute on Aging director Richard J. Hodes, MD, said in a statement.2
The pathogen hypothesis has been one steeped in controversy, with hundreds of published reports claiming an association between AD and bacteria and viruses. Still, the suggestion of a viral contribution to AD has not always been well received by the greater research community.3 “Now, not only is the viral hypothesis resurrected: it has specific testable pathways and networks and interactions that can be explored and reconciled with the rest of the work emerging in Alzheimer’s,” said study coauthor Joel Dudley, PhD, in a statement.4
Researchers at the Icahn School of Medicine in New York and Arizona State University in Tempe conducted RNA sequencing on data from 3 brain banks to evaluate differential viral abundance in AD. The team profiled sample transcriptomes across 4 brain regions — superior temporal gyrus (n=137), anterior prefrontal cortex (n=213), inferior frontal gyrus (n=186), and parahippocampal gyrus (n=107) — from a primary cohort of individuals with AD and controls from the Mount Sinai Brain Bank in order to measure the existence and abundance of 515 viral species that infect humans as a primary host.
The researchers observed multiple viral species in the anterior prefrontal cortex and superior temporal gyrus, most notably an AD-associated increase in HHV-6A and HHV-7. Viral gene-level expression identified increased HHV-6A U3/U4 genes and the HHV-7 direct repeat terminal gene, DR1, in the anterior prefrontal cortex and superior temporal gyrus regions. To confirm their findings, the researchers incorporated additional brain RNA sequencing data from 3 other cohorts comprising individuals with AD, other neurodegenerative diseases, and healthy controls. Once combined, the data revealed a “consistently increased abundance of HHV-6A and HHV-7, driven mainly by the ‘unique’ region of each virus,” the researchers wrote. Further analysis comparing samples from individuals with AD vs those with pathological aging or progressive supranuclear palsy suggest that increased abundance of HHV-6A and HHV-7 are not ubiquitous characteristics of neurodegenerative diseases.
In addition, the team confirmed a correlation between viral load and clinical and neuropathological traits of AD, including clinical dementia rating score and amyloid plaque density.
“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 wrote. They noted, however, that “given the near universal seropositivity for HHV-6 in the general population, seropositivity is likely too non-specific to reliably distinguish AD-relevant states of viral activity within the brain.”
“Follow-up studies that evaluate the onset and progression of AD phenotypes in virally infected AD model systems would be one approach to better delineate the causal and mechanistic relationships that link pathogen activity with the evolution of AD-associated behavioral, molecular, and neuropathological changes,” they concluded.
- Readhead B, Haure-Mirande J-V, Funk CC, et al. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus [published online June 21, 2018]. Neuron. doi: 10.1016/j.neuron.2018.05.023
- NIH-funded study finds new evidence that viruses may play a role in Alzheimer’s disease [news release]. Bethesda, MD; National Institute on Aging. Published June 21, 2018. Accessed June 21, 2018.
- Itzhaki RF, Lathe R, Balin BJ, et al. Microbes and Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):979-984.
- More evidence for controversial theory that herpesviruses play role in Alzhiemer’s disease [news release]. Cell Press. Published June 21, 2018. Accessed June 21, 2018.