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Herpesvirus infections may have a pathogenic link to Alzheimer’s disease

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Does herpesvirus join the list of infective degenerative brain diseases?

The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.

The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.

Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.

Dr. Richard J. Caselli

Second is the concept of a brain microbiome that when disrupted by certain immunosuppressive agents can give rise to progressive multifocal leukoencephalopathy (PML). Viruses live in our brain, normally under control, until something tips the scales in their favor. The time course of both CJD and PML is relatively rapid with few people surviving more than a year, and very unlike the far more slowly progressive course of Alzheimer’s disease whose symptomatic stage can last over a decade and whose preclinical stage may be more than 20 years, according to some studies. The topography of early-stage Alzheimer’s disease bears a striking resemblance to another herpesvirus that the authors did not identify, herpes simplex virus 1, which is the most common cause of viral encephalitis and is limbotropic, targeting the medial temporal lobe and adjacent structures very much like Alzheimer’s disease. Yet evidence relating HSV1 to Alzheimer’s disease has not been conclusive.

The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.

Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.


 

FROM NEURON

Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.

The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS , Jean-Vianney Haure-Mirande, PhD , and colleagues reported June 21 in Neuron.

Dr. Sam Gandy, professor of neurology at Mount Sinai Medical Center, New York

Dr. Sam Gandy

The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.

It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD , director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.

“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”

The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD , one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.

Joel T. Dudley, PhD , director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.

“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”

HHV6

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