Evidence builds of viruses’ role in Alzheimer’s disease
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For more than 30 years, Professor Ruth Itzhaki has been accumulating evidence that viruses — and particularly the common herpes virus HSV-1 — are involved in Alzheimer’s disease.
But persuading the scientific world to take seriously the idea that viral infection plays a big role in degenerative brain conditions has been a struggle for Itzhaki and like-minded researchers. Now, though, she feels the tide of biomedical opinion is turning in their favour, at last.
“So many more observations have emerged recently,” says Itzhaki, who works at Oxford university’s Institute of Population Ageing. Five hundred studies using different approaches have supported the view that viruses play a role in Alzheimer’s disease, she points out.
Susan Kohlhaas, research director of the charity Alzheimer’s Research UK, acknowledges the relationship between viruses and the disease “is an active field of investigation, with lots of things happening”. But she adds: “The jury is still out on quite what the role of viruses is.”
Itzhaki’s most recent study, carried out with colleagues at Tufts University in the US and published in the Journal of Alzheimer’s Disease, demonstrated how HSV-1 could trigger the early stages of dementia by interacting with the related varicella zoster virus (VZV), which causes chickenpox and shingles.
As Itzhaki originally showed in the early 1990s, HSV-1 lies dormant within the brains of many elderly people. Using Tufts’s three-dimensional neural tissue culture to model the brain, researchers found that VZV could activate HSV-1, leading to an accumulation of tau and amyloid proteins and loss of neuronal function — hallmarks of Alzheimer’s. On its own, VZV had little effect.
“Our results suggest one pathway to Alzheimer’s disease: a VZV infection which creates inflammatory triggers that awaken HSV-1 in the brain,” says Dana Cairns of Tufts. “While we demonstrated a link between VZV and HSV-1 activation, it’s possible that other inflammatory events in the brain [such as head trauma] could also awaken HSV-1 and lead to Alzheimer’s disease.”
Clinical trials at Columbia University and New York State Psychiatric Institute, are gathering more direct evidence for the role of HSV-1 in Alzheimer’s. Participants who are in the early stages of the disease and infected with HSV-1 are receiving either valacyclovir, an antiviral herpes drug, or placebo. Completion is expected in December 2023.
Interest in the links between dementia and viruses has also been increased by the Covid-19 pandemic, as evidence accumulates that Sars-Cov-2, the virus responsible for Covid, can affect the brain in some patients.
An extensive study of Sars-Cov-2’s persistent neurological and psychiatric effects was published in August by other researchers at Oxford university. They analysed the electronic health records of 1.25mn people diagnosed with Covid and a matched control group who had other respiratory infections. Among people aged 65 and over, 4.5 per cent of Covid patients developed dementia over the subsequent two years, compared with 3.3 per cent of the control group.
But, as Kohlhaas points out, the first cases of Covid were recorded less than three years ago — and it can take longer for the initial neural triggers to lead to symptoms of Alzheimer’s disease. “We haven’t had enough time to follow through and understand what the implications of Covid are for people who may one day develop dementia,” she says.
Itzhaki suspects that Sars-Cov-2, like VZV, increases the risk of Alzheimer’s by reactivating latent HSV-1 in the brain. People with the gene ApoE4 appear particularly vulnerable. In an effort to assess this, neurologists from 25 countries have set up a global collaboration: the Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of Sars-Cov-2 Infection.
“No available evidence supports the notion that cognitive impairment after Sars-Cov-2 infection is a form of dementia, whether it is Alzheimer’s disease or related dementias or some other cause,” says the consortium’s leader, Gabriel de Erausquin of the University of Texas Health Science Centre at San Antonio. “The . . . multinational initiative will provide data to answer this question as clearly as possible in a globally diverse set of participants.”
Researchers are exploring links between viruses and other neurological conditions, too. “Several papers have appeared recently about viruses and Parkinson’s disease,” says Itzhaki. “And Epstein-Barr virus [EBV] has been implicated in multiple sclerosis.”
A team led by Alberto Ascherio from the Harvard TH Chan School of Public Health studied more than 10mn US military personnel from 1993 to 2013, who had blood samples taken every two years as part of routine medical screenings. The results appeared in the journal Science last January. They compared samples from 800 people who developed MS with 1,500 matched controls who were free of MS. People infected with EBV were 32 times more likely to develop MS than uninfected people. There was no association between MS and other human viruses. “This is the first study providing compelling evidence of causality,” Ascherio says.