'Big data' analysis links herpes virus to Alzheimer's development

The idea that viruses might play a role in Alzheimer's disease is decades old but has never been definitively proven. A "multi-omic" analysis of more than 900 donor brains linked the amount of herpes virus in a person's brain to the presence of Alzheimer's markers, such as amyloid plaques. The discovery could open up new possibilities for Alzheimer's treatment, such as antiviral and immune therapy. 

The researchers, from Arizona State University and the Icahn School of Medicine at Mount Sinai, looked at data from multiple "brain banks" of donor tissue, including whole exome DNA sequencing and RNA sequencing of 622 brains with the clinical and neuropathological features of Alzheimer's disease, and 322 brains without the disease. 

The sequencing provided detailed information about a person's inherited genes and the differences in genetic expression in people with and without Alzheimer's. Clinical assessments of the patients before they died shed light on their cognitive decline, while tests performed after they died provided information on amyloid plaques and tau tangles, which have long been implicated in the disease. 

The team found that brains with Alzheimer's had a high levels of the human herpes viruses (HHV), 6a and 7, while normal brains had lower levels of the two viruses. They also found that herpes viruses played a role in the regulation of amyloid precursor proteins. They believe their findings support the pathogen hypothesis, which posits that amyloid beta builds up in the brain as part of the immune response against infections. 

Their findings were supported in mice. HHV 6a is known to decrease levels of miR155, a regulator of the innate and adaptive immune systems. Depleting miR155 in mice resulted in increased deposition of amyloid plaques and behavioral changes.  

"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," said senior author Joel Dudley, Ph.D., director of the Institute for Next Generation Healthcare at Mount Sinai, in a statement. "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." 

There is a sore need for new hypotheses in Alzheimer's, a field that has relied on beta amyloid and tau proteins as targets. There have been no new therapies for the disease in more than 15 years, and Alzheimer's research is rife with prospects that show early promise but crash and burn in phase 3. 

While the findings, published in the journal Neuron, could give rise to virus or virus-related biomarkers for Alzheimer's, and new pathways to target, the researchers emphasized that the study leaves many unanswered questions. "[The results] don't change anything that we know about the risk and susceptibility of Alzheimer's disease or our ability to treat it today," said co-senior author Sam Gandy, a professor or neurology and psychiatry at Mount Sinai, in a Cell Press statement.

That said, the researchers believe their findings justify further investigation into the pathogen hypothesis of Alzheimer's. "I don't think we can answer whether herpes viruses are a primary cause of Alzheimer's disease. But what's clear is that they're perturbing and participating in networks that directly underlie Alzheimer's pathophysiology," Dudley said.