Two New Triggers for Alzheimer's Identified: What Does it Mean?

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Researchers from Tufts University and the University of Oxford have found that two common viruses—the varicella zoster and herpes simplex viruses—likely constitute a pathway that leads to Alzheimer's disease. 

Their findings, published Tuesday in the Journal of Alzheimer's Disease, suggest that when varicella zoster viruses infect neurons, they trigger an inflammatory response characterized by a surplus of secreted cytokines. In turn, this awakens herpes simplex viruses, which typically lie dormant and harmless in the brain. With both viruses now active, inflammation throughout the brain is aggravated, potentially leading to the formation of plaque and the slow deterioration of neurons—both hallmarks of Alzheimer's.

The research team generated these data by using cultures of neural stem cells, which are able to grow and form networks in the lab as they would in the brain. Interestingly, they found that infecting neurons with varicella zoster alone was not enough to trigger Alzheimer-like properties in their setup. When herpes simplex was already lying in wait, varicella zoster initiated a cascade of events that culminated in plaques, tangled fibers and brain damage.

"It's a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble," Dana Cairns, research associate at the Biomedical Engineering Department of Tufts, said in a statement. Cairns is the study's lead author. One of their collaborators, Oxford's Ruth Itzhaki, was one of the first scientists to suggest a link between herpes infections and Alzheimer's.

HSV-1, the subtype of the herpes simplex virus thought to be involved in Alzheimer's, causes both oral and genital herpes. It is a very common infection, affecting nearly 4 million people worldwide under the age of 50 years. The American Sexual Health Organization estimates that around one in two adults has oral herpes in the United States. 

Varicella zoster, the other half of the pathway uncovered by Cairns' group, is also an extremely common virus. The first infection with varicella zoster causes chickenpox, but after that's cured, the virus tends to linger in peripheral nerves. When these quiescent viruses are reactivated, they cause shingles.

Those highly prevalent viruses could lead to Alzheimer's doesn't bode well for a therapeutic space that has of late been strapped with trial failures and scientific scandals.

Earlier this week, Roche subsidiary Genentech and its partner AC Immune had to dig deep into Phase II data after their candidate, crenezumab, fell short of its primary endpoint in patients with autosomal dominant Alzheimer's disease. Failing to show significant superiority over placebo in cognitive and memory measures, the companies instead diverted attention toward a positive trend in the data and blamed the lack of statistical significance on what AC Immune called "a confluence of factors."

Even the first-ever drug approved for Alzheimer's, Biogen's Aduhelm (aducanumab), has had a difficult time taking off, with many skeptics questioning its efficacy. In June this year, following drastically curtailed insurer coverage of their drug, the company decided to let go of a post-market real-world analysis of Aduhelm. A Phase IV confirmatory trial is pushing through.

Aside from major medication misses, allegations of data falsification have also rocked the Alzheimer's space. At the center of one such controversy is the Texas biotech Cassava Sciences, which last month had a DOJ investigation opened against it. The probe will focus on claims that the company had doctored data to support its Alzheimer's drug simufilam. Cassava has been embroiled in this matter for almost a year now.

Alongside the Cassava controversy is another that casts doubt on a seminal 2006 paper, published in the prestigious medical journal Nature. Science sleuths have found evidence that Western blot photos were manipulated, calling into question the role of Aβ*56—an amyloid-β oligomer—in the signature memory loss tied to Alzheimer's.

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