From the economist.

I’ve been aware of the lower risk of Alzheimers in those who have had a shingles vaccine for some years . In fact, that was a major reason I paid for the vaccine a few years back (it is now free for >50 year olds). But this review really fleshes out that theory.

Initially, I thought it was a thesis buster given this will impact the beta amyloid theory and all the current crop of drugs. Having slept on it, I realise it may well be a positive: more research, more cognitive assessments, more business for Cogstate. Interested in others thoughts:

n the summer of 2024 several groups of scientists published a curious finding: people vaccinated against shingles were less likely to develop dementia than their unvaccinated peers. Two of the papers came from the lab of Pascal Geldsetzer at Stanford University. Analysing medical records from Britain and Australia, the researchers concluded that around a fifth of dementia diagnoses could be averted through the original shingles vaccine, which contains live varicella-zoster virus. Two other studies, one by GSK, a pharmaceutical company, and another by a group of academics in Britain, also reported that a newer “recombinant” vaccine, which is more effective at preventing shingles than the live version, appeared to confer even greater protection against dementia.

For years, most research into Alzheimer’s disease—the most common cause of dementia—has been laser-focused on two proteins, known as amyloid and tau. These build up in the brains of people with the disease, forming plaques and tangles that prevent neurons from functioning properly. Most scientists assumed that these proteins are the primary cause of Alzheimer’s disease. But the shingles studies published in 2024, along with a host of new papers, add weight to an alternative decades-old idea—that viruses trigger the disease. Per this theory, plaques and tangles of proteins could, instead, be the body’s response to an underlying viral infection. If that is true, then eliminating the virus could prevent or treat Alzheimer’s.

Ruth Itzhaki, formerly of Manchester University and now a visiting professor at the University of Oxford, has championed this idea for almost 40 years. The bulk of her work has focused on herpes simplex virus 1 (HSV1), best known for giving people cold sores, which infects around 70% of people, most without symptoms. The virus normally lives outside the brain, where it can lie dormant for years. It is flare-ups that can lead to cold sores.

In rare cases, the virus can also lead to massive inflammation in the same brain areas that are most affected by Alzheimer’s. In experiments conducted in the early 2000s, Professor Itzhaki found that if she infected lab-grown human brain cells with HSV1, amyloid levels inside the cells increased dramatically. That led her to suspect a causal connection.

For decades she struggled to get her ideas accepted by the rest of the scientific community. “It was considered a left-field, crazy hypothesis,” says Or Shemesh, who researches viruses and Alzheimer’s at the Hebrew University of Jerusalem. Most scientists were focused on the role of amyloid and tau, assuming that they were the primary cause of the disease. Critics argued that the virus theory was hard to reconcile with the fact that Alzheimer’s has a strong genetic basis or occurs in almost all people with Down’s syndrome.

But growing disillusionment with the leading hypothesis for the cause of Alzheimer’s has led scientists to cast around for alternatives, such as viruses. Over many decades, for example, tens of billions of dollars have been poured into efforts to develop treatments to reduce the levels of amyloid and tau in the brain but the results have been underwhelming—existing amyloid-targeting drugs only have a modest effect on the disease. The discovery that pathogens can trigger other neurological diseases, such as the connection between Epstein-Barr virus and multiple sclerosis, has made the link yet more plausible.

In a bid to push forward Professor Itzhaki’s theory, a group of 25 scientists and entrepreneurs from around the world have assembled themselves into the Alzheimer’s Pathobiome Initiative (AlzPI). Their mission is to provide formal proof that infection plays a central role in triggering the disease. In recent years their work detailing how viruses trigger the build up of proteins linked to Alzheimer’s has been published in top scientific journals.

One new idea, supported by some AlzPI members, is that amyloid and tau may actually be the brain’s first line of defence against pathogens. These proteins are sticky, so they can grab hold of viruses or bacteria to slow their spread before more sophisticated immune responses kick in, says William Eimer at Harvard University. In small quantities, therefore, the proteins seem to boost brain health. The presence of active HSV1 or other pathogens, however, may send the immune system into overdrive, causing the proteins to stick to each other and create the plaques and tangles that damage neurons in Alzheimer’s.

Genetics seem to influence this process, answering some criticisms. The high incidence of the disease in those with Down’s syndrome, for example, might be explained by the fact that their bodies produce more of the protein that is, under certain conditions, converted into amyloid. Some of the AlzPI scientists theorise that this larger potential supply of amyloid could facilitate the formation of plaques in response to a virus. People with Down’s are also more prone to infection.

What’s more, in 1997 Professor Itzhaki found that people with a genetic variant known to increase Alzheimer’s risk, ApoE4, were only more likely to get the disease if they also had HSV1 in their brain. In 2020 a group of French scientists showed that repeated activations of the virus, seemingly harmless in people without ApoE4, more than tripled the chance of developing Alzheimer’s in those with it.

Researchers at Tufts University, working with Professor Itzhaki, have probed why such reactivation occurs. In 2022 they found that infection with a second pathogen, the shingles virus, could awaken the dormant HSV1 and trigger the accumulation of plaques and tangles. This may explain why shingles vaccination appears to be protective against dementia. In another study published in January, the Tufts researchers also showed that a traumatic brain injury—a known risk factor for Alzheimer’s—could also rouse HSV1 and start the aggregation of proteins in brain cells grown in a dish.

The viral theory has promising implications for treatment. Current therapies for Alzheimer’s, which attempt to reduce levels of amyloid in brain cells, merely work to slow the progression of the disease. If viruses are a trigger, though, then vaccination or antiviral drugs could prevent future cases. Such treatments could also slow or halt the progression of Alzheimer’s in those who already have the disease. None of this requires major breakthroughs. Antivirals for the cold-sore pathogen already exist and are off-patent. And the shingles vaccine is now routinely offered to elderly people in many countries.

Many researchers have trawled through medical records to look for links between antivirals and reductions in dementia diagnoses. These sorts of retrospective analyses are often tricky to interpret, as people who take medications or get vaccinations tend to be more health-conscious in general, making them less likely to develop diseases such as Alzheimer’s. But some of the results are promising. One study published in 2018 found that for older people in Taiwan who had cold sores, taking an antiviral cut the risk of dementia by 90%. Several subsequent analyses of medical data from other countries found more modest protective effects of antivirals, typically between 25 and 50%.

 The first double-blinded randomised clinical trial to test the effectiveness of antivirals against dementia is now under way. A group of researchers mostly based at Columbia University are testing whether valacyclovir, an antiviral used against HSV1, can slow down cognitive decline in people with early stage Alzheimer’s. Between 2018 and 2024, the researchers recruited 120 patients and treated half with the antiviral. They expect to publish their findings later this year. John Hardy, whose research forms the basis of the dominant amyloid theory of Alzheimer’s, and who has been a critic of the virus theory, says that a positive result in this trial would begin to convince him otherwise. If Dr Geldsetzer and his team can secure the funding, a similar trial of the shingles vaccine may soon follow.

Around 32m people around the world are living with Alzheimer’s disease. If antiviral treatments can indeed slow, delay or prevent even a small subset of these cases, the impact could be tremendous. ■