Evidence is growing on the role of viruses in Alzheimer’s disease

For more than 30 years, Professor Ruth Itzhaki has been gathering evidence of the involvement of viruses in Alzheimer’s disease, especially the common herpes virus, HSV-1.

But persuading the scientific world to take seriously the idea that a viral infection plays a role in degenerative brain conditions has been a challenge for Itzhaki and other scientists who follow his train of thought. Now, however, she thinks the tide of biomedical opinion is finally turning in their favor.

“A lot more observations are coming to light,” said Itzhaki, who works at Oxford University’s Institute on Population Aging. She points out that 500 studies using different approaches reinforce the view that viruses play a role in Alzheimer’s disease.

Susan Kohlhaas, director of research at the non-profit Alzheimer’s Research UK, admits that the virus-disease link “is a field under active investigation where there’s a lot going on.” However, she points out, “there is still no consensus on what the role of viruses is”.

Itzhaki’s most recent study was done with her colleagues at Tufts University in the United States and published in the Journal of Alzheimer’s Disease. The work demonstrated how HSV-1 can trigger the early stages of dementia by interacting with the related varicella-zoster virus (VZV), responsible for chickenpox (chickenpox) in children, and herpes zoster, also known as shingles.

As Itzahki originally demonstrated in the early 1990s, HSV-1 remains dormant in the brains of many elderly people. Using Tufts’ three-dimensional neural tissue culture to model the brain, researchers found that VVZ can activate HSV-1, leading to an accumulation of tau and amyloid proteins and loss of neuronal function, hallmarks of Alzheimer’s disease. Alone, the VVZ had little effect.

“Our results suggest a pathway to Alzheimer’s disease: a VZV infection that creates inflammatory triggers that activate HSV-1 in the brain,” said Dana Cairns of Tufts University. “We have demonstrated the existence of a link between VZV and HSV-1 activation, but it is possible that other inflammatory brain events (such as head trauma) can also arouse HSV-1 and lead to Alzheimer’s disease.”

Clinical trials underway at Columbia University and the New York State Psychiatric Institute are gathering more direct evidence of HSV-1’s role in Alzheimer’s. Participants who are in the early stages of the disease and are infected with HSV-1 are receiving either valaciclovir, an antiviral herpes drug, or a placebo. Trials are expected to be completed in December 2023.

Interest in the links between dementia and viruses has also increased with the Covid-19 pandemic, with evidence accumulating that Sars-Cov-2, the virus responsible for Covid, can affect the brains of some patients.

An extensive study of the persistent neurological and psychiatric effects of Sars-Cov-2 was published in August by other Oxford University scientists. They analyzed the electronic medical records of 1.25 million people diagnosed with Covid and a control group who had other respiratory infections. Among people aged 65 and over, 4.5% of Covid patients developed dementia in the subsequent two years, compared to 3.3% in the control group.

But, as with this Kohlhaas, the first Covid cases were recorded less than three years ago, and it can take longer than that for initial neural triggers to lead to Alzheimer’s disease symptoms. “We haven’t had enough time to follow up and understand the implications of Covid for people who could one day develop dementia,” she said.

Itzhaki suspects that Sars-Cov-2, like VVZ, increases the risk of Alzheimer’s by reactivating latent HSV-1 present in the brain. People with the ApoE4 gene appear to be especially vulnerable. In an effort to assess this hypothesis, neurologists from 25 countries created a global collaboration: the Alzheimers Association Consortium on the Chronic Neuropsychiatric Sequelae of Sars-Cov-2 Infection.

“No available evidence supports the idea that cognitive impairment following a SARS-Cov-2 infection is a form of dementia, whether it’s Alzheimer’s disease, related dementias or some other cause,” says consortium leader Gabriel de Erausquin of the University of Texas Health Science Center at San Antonio. “The multinational initiative will bring data to answer this question as clearly as possible across a globally diverse set of stakeholders.”

Researchers are also studying links between viruses and other neurological conditions. “Recently, there have been a lot of articles about viruses and Parkinson’s disease,” says Itzhaki. “And the Epstein-Barr virus (EBV) has been linked to multiple sclerosis.”

A team led by Alberto Ascherio of the Harvard T.H. Chan School of Public Health studied more than 10 million US military personnel between 1993 and 2013 who had blood samples taken every two years as part of routine medical examinations. The results came out in January in the journal Science.

The team compared samples from 800 people who developed MS with 1,500 control people without MS. People infected with EBV were 32 times more likely to develop multiple sclerosis than non-infected people. No link has been found between multiple sclerosis and other human viruses. “This is the first study that brings convincing evidence of causality,” says Ascherio.

^{Translation by Clara Allain}