Recent findings suggest chronic infections, notably herpes, might play a crucial role in triggering Alzheimer's disease. Photo / 123rf
For decades, the predominant focus of almost all Alzheimer’s research has been on two protein fragments, beta-amyloid and tau, which are found to accumulate in the brains of patients, triggering the onset of symptoms such as memory loss.
Yet exactly how and why these proteins begin to congregate in the brain remains a mystery, but in recent years, evidence has begun to steadily accrue for a new theory – could chronic infections be triggering the damage which leads to Alzheimer’s?
Earlier this month, a new study from neurologists at Columbia University in New York studied MRI scans and blood tests from 455 adults with an average age of 70. They found those who tested positive for herpes simplex virus 2 (HSV-2), otherwise known as genital herpes, displayed shrinkage in a critical layer of the brain called the cerebral cortex, which is involved in memory and language, a sign of cognitive decline.
According to Dr Davangere Devanand, a neurologist at Columbia University who is investigating whether herpes antivirals can offer benefit to Alzheimer’s patients, it is thought herpes may ultimately invade the brain as the immune system weakens later in life.
“Once you contract herpes, the virus actually stays in your body forever, it never goes away,” he says. “People who get the infection may recover from it, but we know that for some reason the virus likes to travel to a region at the base of the skull called the trigeminal ganglion. From there it can very easily get to the brain and cause some degree of damage.”
While many doctors and neuroscientists have only begun to take the idea more seriously in recent years, Devanand says the evidence linking different strains of the herpes virus – not just genital herpes but also oral herpes or herpes simplex virus 1 – to Alzheimer’s goes back to the 1980s.
“There were some investigations in animal models, showing that when the herpes virus was injected into cells, they were more likely to form clumps of amyloid which is what occurs in Alzheimer’s,” he says. “And then people looked at the brains of Alzheimer’s patients after they’d died and found that herpes virus DNA was present in much higher levels.”
In the past decade, population studies in the UK, France and Scandinavia have all reported that people who test positive for herpes are more at risk of developing the disease. One eye-catching study in Taiwan, published in 2018 in a journal called Neurotherapeutics, showed that when middle-aged or older adults were treated with herpes antivirals, their risk of cognitive decline was reduced ninefold.
Rudolph Tanzi, the Harvard neurologist, has developed his own theory as to how a viral infection leads to the formation of toxic amyloid plaques and tau tangles, the distinct hallmarks of Alzheimer’s. He says amyloid and tau, far from being villains, are initially there to protect us, helping to entangle and trap rogue microbes in the brain, allowing the brain’s immune system to clear them during deep sleep.
“Viruses like herpes spread neurotropically, meaning they move from neuron to neuron,” he says. “We’ve learnt that tau tangles can prevent them from doing this. Our research suggests that when you have a virus in the brain, first beta-amyloid binds to it and tries to trap it. If it gets away, a tau tangle will be triggered.”
If these tangles and plaques aren’t cleared by the immune system, they can prove toxic to our brain’s cells over time. Tanzi believes that because of genetic vulnerabilities – such as the APOE4 gene variant which is heavily linked to Alzheimer’s – or simply the ravages of ageing, the immune system can get sluggish, allowing this debris to slowly build.
Herpes is far from the only pathogen to have been linked with Alzheimer’s. Nikki Schultek has launched Alzheimer’s Pathobiome Initiative, a global interdisciplinary collaboration, to promote research into the connection between infections and the disease.
“There’s compelling epidemiological research,” she says. “As well as herpes viruses, the Lyme disease-causing bacteria Borrelia burgdorferi, bacteria like chlamydia pneumoniae [which cause respiratory infections such as pneumonia] and oral bacteria such as Porphyromonas gingivalis [which causes chronic gum disease known as periodontitis] have been strongly associated.”
Last year, a review paper in the Journal of the American Geriatrics Society concluded that poor oral health is associated with brain degeneration over time. Like herpes, Porphyromonas gingivalis bacteria have also been identified in amyloid plaques inside the brains of Alzheimer’s patients.
Tomas Welsh, research and medical director at the Rice Institute in Bath, says some bacteria can secrete enzymes that may be capable of helping them burrow into the brain.
“These bugs can work their way into the bloodstream, get to the brain where they start an inflammatory response, and the brain starts to develop some amyloid and tau tangles as part of that,” he says.
There are even suggestions some gut infections such as C diff, a germ that causes diarrhoea and colitis, may be linked to Alzheimer’s. Yvonne Nolan, a professor in anatomy and neuroscience at University College Cork, is particularly interested in how shifts in the microbiome mediated by these infections could contribute to cognitive decline.
“Changes in the gut microbiome have been repeatedly shown to influence and regulate cognitive and memory behaviours,” she says. “We found that transferring gut microbiota from Alzheimer’s patients in a process called faecal microbiota transplantation to young rats caused the rats to perform poorly in certain memory tests.”
While there is no vaccine for HSV-1 or HSV-2, researchers believe the emerging evidence linking pathogens with cognitive decline points to the importance of other midlife vaccinations, for example the shingles vaccine.
Research has indicated that the varicella zoster virus which causes shingles may be capable of reactivating oral herpes from a dormant state, and one study found that people who had received the jab were less at risk of Alzheimer’s.
According to Welsh, the evidence linking gum disease and brain health points to the importance of regular dental appointments and good oral hygiene to prevent the build-up of plaques, which act as a home for the bacteria.
“It’s been established for many years now that poor dental health and more gum disease means your risk of Alzheimer’s progressing is much higher,” he says.
Nolan also points to simple lifestyle measures such as exercise and consuming a high-fibre diet to ensure your gut is nourished with the right fuel to fight off potentially harmful pathogens.
“Given that it is becoming increasingly recognised that Alzheimer’s is substantially influenced by lifestyle and environmental factors, changing the composition of gut microbiota through diet or other lifestyle factors like exercise, or by administering substances like prebiotics, may help,” she says.
Perhaps most excitingly, these findings could point to an entirely different way of treating the disease. In a paper published in the Journal of the Alzheimer’s Association earlier this year, Schultek highlighted case reports of various dementias including Alzheimer’s which appeared to be caused by certain microbes.
“They were quite varied – bacteria, viruses, fungi, parasites and infections with more than one germ found in spinal fluid,” she says. “Some of these people responded to tailored antimicrobial treatment, restoring cognitive function.”
Dr Devanand is now looking to study this more rigorously through an ongoing clinical trial investigating whether a herpes antiviral drug called valaciclovir can slow down Alzheimer’s progression in patients in the early stages of the disease. If it demonstrates any benefit, this could even lead to herpes antivirals being offered to people in midlife or initiate new efforts to develop effective herpes vaccines.
Other researchers are looking at new ways of targeting harmful gum bacteria and Welsh points to San Francisco-based biotech Quince Therapeutics, which has developed a drug capable of blocking the action of some of the enzymes secreted by these bacteria. But while the therapy worked successfully in mice that had been engineered to show characteristics of Alzheimer’s, it failed when trialled in humans.
“I believe they’re developing some new molecules to try to pursue this hypothesis further,” says Welsh. “So I think this is still an exciting and cutting-edge area of research. Our centre is keen to be involved in further trials and we’ve been having some conversations with the Bristol dental school, which is interested in this area. It would be fantastic if we can find another solution to this disease.”
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