Could an infection like the common cold sore virus lead to dementia? 

Scientists are investigating if certain viruses and bacteria can cause dementia in later life. Other scientists are looking at ways an anti-inflammatory lifestyle could minimise the risk of these pathogens damaging the brain

Neuroscientist Colm Cunningham, TCD: ‘Encourage older people to continue flu-vaccination.’

Are infections responsible for dementia?

At Trinity College Dublin, neuroscientist Colm Cunningham has spent years attempting to unravel the apparent connection between episodes of delirium —sudden changes in a person’s mental state, ranging from confusion to drowsiness — and the onset of dementia.

He was intrigued that this delirium appeared to be triggered by an infection.

“Episodes of delirium often occur with infection in older people and these events accelerate the subsequent appearance of cognitive decline and shorten the time to dementia,” Cunningham says.

These findings represent yet another piece in a complex puzzle that links some cases of dementia to various microbes, ranging from viruses to bacteria to parasites, and even fungal infections.

This may point to ways of slowing the progression of dementia and preventing its onset.

An estimated 64,000 people in Ireland have dementia and it’s predicted that this number will have more than doubled, to 150,000, by 2045, as the population ages. However, there are still no effective treatments for the many different forms of the disease. This is an enormous economic burden on our healthcare systems: Dementia care costs the country around €2bn every year.

Over the last 40 years, pioneering scientists, such as Professor Ruth Itzhaki, at the University of Oxford, have accumulated evidence linking pathogens — such as the common herpes simplex virus 1 (HSV-1), which causes cold sores; and a species of oral bacteria, called Porphyromonas gingivalis — to cognitive decline. For decades, this work was largely overlooked by mainstream dementia scientists, until new findings connecting pathogens to chronic diseases — such as last year’s discovery that the Epstein-Barr virus is the leading cause of multiple sclerosis — have made it impossible to ignore.

Experts say there are many reasons why pathogens could cause dementia. The first is linked to so-called hit-and-run infections, like SARS-CoV-2, which invade organs, wreaking havoc in their wake. A severe bacterial or viral infection that becomes septic can cause injury to the brain, with a recent study showing that infections resulting in hospitalisation double the risk of dementia in the subsequent five years.

“Such an infection could damage a significant amount of brain reserve,” says Cunningham. “This means the loss of synapses, axons, or neurons, causing age-related decline to become apparent at a younger age, and increasing the risk of dementia in later life.”

There are also ‘hit and stay’ infections that silently assimilate within the body’s tissues and stay for years or even decades. But as the immune system weakens in later life, these infections can awaken and move into the brain. This is one of the major theories linking HSV-1 to dementia. Itzhaki has found evidence that the Varicella zoster virus, which causes shingles, could reactivate HSV-1 from a dormant state.

It may not just be one pathogen that is responsible for dementia. The impact of multiple infections over the course of a lifetime could cause a slow build-up of inflammation in the body, affecting brain function over time.

This may be responsible for the episodes of delirium, which some patients experience as an early sign of cognitive decline.

“Infectious agents have been found in the brains of Alzheimer’s patients,” says Yvonne Nolan, a professor in anatomy and neuroscience at University College Cork. “These pathogens can travel across the blood-brain barrier from the nasal and oral cavity, or via the bloodstream to precipitate or exacerbate brain inflammation.”

Our growing realisation of the long-term impact of these infections could offer a new pathway for treating this incurable disease.

Neuroscientist Colm Cunningham, TCD

Clinical trials

At Columbia University Medical Center, a pivotal clinical trial is under way, investigating whether a herpes antiviral drug, called valacyclovir, can slow the progression of Alzheimer’s — the most common form of dementia — in patients in the early stages of the disease.

This is just the first of many projects to determine whether knocking out a particular pathogen can hold benefits for dementia patients. Keystone Bio, a biotech company in St Louis, in the US, is designing drugs to target the Porphyromonas gingivali bacteria to see if this reduces inflammation in the brain.

According to Nikki Schultek, a former Pfizer employee who now runs The Alzheimer’s Pathobiome Initiative, a global collaboration investigating microbial causes of the disease, it may even be possible to reverse symptoms of cognitive decline in some cases. “Our review of the medical literature showed at least 20 cases of reversible dementia caused by infection,” says Schultek. “The majority of patients were restored to a normal level of memory, if the doctor tested and treated the underlying infections. This suggests that there is a group of patients walking around that could be treated.”

Cunningham cautions that for many patients, earlier interventions may be necessary to halt or reverse the disease. By the time they have received a dementia diagnosis, the level of brain damage may already be too advanced.

“It is important to manage expectations, because any trial conducted after disease is already underway may fall the way many dementia trials have in the past,” he says. “If the disease cascades have begun, then reversing this process is going to be difficult.”

However, the increasing evidence of microbial involvement in dementia presents a case for offering people more preventative vaccines against different viruses in mid-life. For example, people who get a shingles vaccine have a slightly lower risk of developing dementia.

“I think there is a strong case to encourage older people to continue flu-vaccination programmes as one way of fending off the effects of infections on the brain integrity,” says Cunningham. “Adding other specific vaccines to this list is possible, but we need to build more confidence about which viruses or bacteria may be contributing to cognitive decline.”

Prof Yvonne Nolan, UCC

Gut microbiome link

As a funded investigator with APC Microbiome Ireland, Nolan is examining how the communities of bacteria within the gut microbiome affect the risk of developing dementia in later life.

Research is ongoing into whether external infections or lifestyle factors can disrupt the microbiome in mid-life, placing the body in an inflammatory state and making individuals more vulnerable to cognitive decline as they age.

Because long-term use of anti-inflammatory drugs in mid-life has also been shown to be protective against dementia, researchers are increasingly interested in whether other interventions aimed at reducing inflammation in the body, such as exercising or taking prebiotics, can prevent this kind of mental deterioration from happening in the first place.

In collaboration with scientists at King’s College London, Nolan is working on a project looking into how the gut microbiome and brain respond to exercise in middle age.

The aim is to see whether people who commit to a regular exercise regimen in their 40s, 50s, and 60s experience positive changes in their microbiome composition, protecting them against dementia in decades to come.

“It is becoming increasingly recognised that Alzheimer’s, in particular, is a disease which is substantially influenced by lifestyle and environmental factors,” she says.

“So changing the composition of the gut microbiota, through diet, exercise, or even administering substances like prebiotics to help clusters of identified microbes that act in an anti-inflammatory capacity to thrive in the gut, may help to tackle the disease, or at least parts of it.”