Research 'most compelling evidence ever' of viral trigger for Alzheimer's

Prof Riona Mulcahy and Prof John Nolan

Doctors don't know what causes Alzheimer's disease or the best way to treat it, but they have new evidence to suggest that a common virus may play a role in who develops the condition. "We needed to search for sequences from hundreds of different viruses, so having access to that raw, unprocessed data was absolutely key", says first author Ben Readhead. "We were looking for genes that were dysregulated during the progression of Alzheimer's disease".

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks. Skeptical researchers have hunted for other explanations, and some have zeroed in on microbes.

Some scientists have long believed that viruses play a role in the development of Alzheimer's.

Much of the research described in the new study was performed in the laboratory of Joel Dudley, associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, associate research professor in the NDRC, and senior author of the paper in Neuron.

They began by sequencing DNA from the dead patients to find out information about inherited genes, followed by finding out how those genes were expressed. That's when they started getting odd results.

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HAMILTON: And Dudley says what they found was really intriguing.

The data provide compelling evidence that these specific viral species contribute to the development of neuropathology and Alzheimer's disease. The viruses "seemed to be talking to some of the networks that contained some of the familiar Alzheimer's-related genes". But we were able to do statistical causal inference testing and more sophisticated analysis, which allowed us to identify how the viruses are directly interacting with or coregulating or being regulated by Alzheimer's genes. When they later bred mice deficient in this microRNA, they found that the rodents developed larger and more abundant amyloid plaques in their brains than did mice with normal microRNA levels.

The Alzheimer's community remains cautious about the findings.

Dr James Pickett, head of research at Alzheimer's Society, said: "The relationship between viruses and Alzheimer's disease has been an area of interest for researchers for a while, but it is still unclear if higher levels of viruses cause dementia or are caused by it".

"Previous studies of viruses and Alzheimer's have always been very correlative".

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"When we started analyzing the differences, it just sort of came screaming out at us from the data", Dudley says. Hodes says the new research on viruses also hints at another way to fight Alzheimer's.

Experts have strongly condemned "irresponsible" and "deeply cynical" claims that a new food supplement can slow the progress of Alzheimer's.

But a team led by researchers at New York's Mount Sinai Health System found that certain viruses - including two extremely common herpes viruses - affect the behavior of genes involved in Alzheimer's. 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 researchers believe that their findings align with other current research in the Alzheimer's field on the role of innate immunity in the disease, particularly recent findings that beta-amyloid protein-the culprit behind the plaques that build up in the Alzheimer's-affected brain-may accumulate as part of a defense against infections.

This is especially true because HHV-6A and HHV-7 are extremely common and often latent or asymptomatic: in North America, nearly 90% of children have one of these viruses circulating in their blood by the time they're a few years old. That's tricky, he says, because simply disabling the brain's immune cells could be harmful. Ruth Itzhaki, a neurobiologist at the University of Manchester in the United Kingdom, who has led numerous studies linking HSV-1 with Alzheimer's, says she has suffered "derision and vituperative hostility" for pursuing this line of inquiry.

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But Dudley is willing to accept the risks and push forward. "Look, my life would be easier, too, if we hadn't found these viruses", he says.

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