An unusual health policy in Wales may have provided the strongest evidence yet that a vaccine can reduce the risk of dementia. In a new study led by Stanford Medicine, researchers analyzed the health records of older Welsh adults and found that those who received the shingles vaccine were 20% less likely to develop dementia over the next seven years than those who did not get the vaccine. The remarkable findings, published in Nature, support the emerging theory that viruses that affect the nervous system can increase the risk of dementia. If these new findings are confirmed, they suggest that a preventive measure against dementia is already within reach.
The Role of Certain Viral Infections in Dementia
Shingles, a viral infection that causes a painful rash, is caused by the same virus that causes chickenpox – varicella-zoster. After people have contracted chickenpox, usually in childhood, the virus remains inactive in the nerve cells for life. In older people or people with a weakened immune system, the dormant virus can be reactivated and cause shingles. Dementia affects more than 55 million people worldwide and an estimated 10 million new cases are diagnosed every year. Decades of dementia research have largely focused on the accumulation of plaques and deposits brain of people with Alzheimer’s, the most common form of dementia. However, in the absence of breakthroughs in prevention or treatment, some scientists are exploring other avenues – including the role of certain viral infections.
Previous studies based on health records have linked the shingles vaccine to lower rates of dementia, but failed to account for an important cause of bias: People who are vaccinated also tend to be more health-conscious in a variety of ways that are difficult to measure. Behaviors such as diet and exercise are known to influence dementia rates, but are not included in health records. “All of these associative studies suffer from the fundamental problem that people who get vaccinated have different health behaviors than people who don’t,” said Pascal Geldsetzer, MD, PhD, assistant professor of medicine and lead author of the new study. In general, they are not considered robust enough to make recommendations.
Analyzing the Health Records of More Than 280,000 Older Adults
Two years ago, however, Geldsetzer recognized an accidental “natural experiment” in the introduction of the shingles vaccine in Wales that seemed to circumvent the bias. The vaccine used at the time contained a weakened form of the virus. The vaccination program, which began on September 1, 2013, stipulated that anyone who was 79 years old on that date was eligible for the vaccine for one year. (People who were 78 were eligible for a year the next year, and so on.) People who were 80 or older on September 1, 2013, were out of luck – they would never be eligible for the vaccine. These rules, which served to ration the limited vaccine supply, also meant that the slight difference in age between 79 and 80-year-olds determined who had access to the vaccine. By comparing people who turned 80 shortly before September 1, 2013, with people who turned 80 shortly after, the researchers were able to isolate the effect of vaccine eligibility. The circumstances, which are well documented in the country’s health records, were as close to a randomized controlled trial as was possible without one, Geldsetzer said.
The researchers examined the health records of more than 280,000 older adults aged 71 to 88 who did not have dementia at the start of the vaccination program. They focused their analysis on those who were closest to the eligibility threshold, comparing people who turned 80 the week before with people who turned 80 the week after. “We know that on average there should be no differences between a thousand randomly selected people born in one week and a thousand randomly selected people born a week later,” Geldsetzer said. They are similar except for that tiny age difference. The same proportion of both groups would likely have wanted to receive the vaccine, but only half, the nearly 80-year-olds, were allowed to because of licensing rules. What makes the study so meaningful, according to the researchers, is that it was essentially conducted like a randomized trial with a control group – those a little too old to be eligible for the vaccine – and an intervention group – those just young enough to be eligible.
Link Between Vaccination and Lower Dementia Rates
Over the next seven years, the researchers compared the health outcomes of people who were closest in age to each other and who were and were not eligible for the vaccine. By considering actual vaccination rates – about half of the eligible population received the vaccine, while almost none of those who were not eligible were vaccinated – they were able to infer the effects of the vaccine. As expected, the vaccine reduced the incidence of shingles by about 37% over this seven-year period in those who were vaccinated, similar to what had been found in the clinical trials of the vaccine. (The efficacy of the live attenuated vaccine diminishes over time). By 2020, one in eight older adults, who were 86 and 87 years old at the time, had been diagnosed with dementia. However, those who had received the shingles vaccine were 20% less likely to develop dementia than those who had not been vaccinated.
The scientists looked everywhere for other variables that might have influenced the risk of dementia, but found that there was no difference between the two groups in any characteristics. For example, there was no difference in educational attainment between those who were eligible and those who were not. Those who were eligible were not more likely to receive other vaccinations or preventive treatments, nor were they less likely to be diagnosed with other common health problems such as diabetes, heart disease and cancer. The only difference was the decrease in dementia diagnoses. Nevertheless, the research team analyzed the data in different ways – for example, using different age groups or looking only at deaths attributable to dementia – but the link between vaccination and lower dementia rates remained.
Stronger Response in Women
Another finding of the study was that protection against dementia was much more pronounced in women than in men. This could be due to gender-specific differences in the immune response or in the way dementia develops, according to Geldsetzer. For example, women on average have a stronger antibody response to vaccinations and shingles is more common in women than in men. It is still unknown whether the vaccine protects against dementia by boosting the immune system as a whole, by specifically reducing the reactivation of the virus or by some other mechanism. It is also unknown whether a newer version of the vaccine, which contains only certain proteins of the virus and prevents shingles more effectively, could have a similar or even greater effect on dementia. Geldsetzer hopes that the new findings will lead to more funding for this area of research.
“Investing at least some of our resources in researching these pathways could lead to breakthroughs in treatment and prevention,” Geldsetzer said. Over the past two years, his team has replicated the findings from Wales in health records from other countries, including England, Australia, New Zealand and Canada, which have conducted similar vaccination campaigns. However, the researchers have set their sights on a large randomized controlled trial, which would provide the strongest evidence of cause and effect. Participants would be randomized to receive either the live vaccine or a placebo vaccination. And such a study could soon deliver results.