MADRID, Dec. 2 (EUROPA PRESS) –

For years, experts have suspected that certain viruses might influence brain health more than we think. But now, an almost accidental health policy in a small European country has opened an unexpected window to understand that connection. What seemed like a simple logistical decision has allowed us to observe patterns that until now were invisible.

In the midst of that unique opportunity, an international team of researchers has analyzed thousands of medical records to pursue a lead that could change the way we understand the risk of cognitive decline. The results, far from being anecdotal, point to a relationship that the scientific community had been searching for for some time, and that could have much broader implications than previously thought.

AN UNEXPECTED POLICY THAT REVEALED SOMETHING NO ONE WAS LOOKING FOR

An unusual public health policy in Wales may have generated the strongest evidence yet that the shingles vaccine can reduce the risk of dementia. Specifically, in a new study led by Stanford Medicine (United States), researchers who analyzed the medical records of older Welsh adults found that those who received the shingles vaccine were 20% less likely to develop dementia in the following seven years than those who did not receive it.

The remarkable findings, published in Nature, support an emerging theory that viruses that affect the nervous system may increase the risk of dementia. If confirmed, the new findings suggest that a preventive intervention for dementia is now within reach.

In a follow-up study published in Cell, researchers found that the vaccine may also benefit those already diagnosed with dementia by slowing the progression of the disease.

WHAT RESEARCHERS DISCOVERED AFTER ANALYZING THOUSANDS OF STORIES

Previous studies based on medical records have linked the shingles vaccine with lower rates of dementia, but they failed to explain an important source of bias: Vaccinated people also tend to be more conscious of their health in multiple, hard-to-measure ways. Habits such as diet and exercise, for example, are known to influence dementia rates, but they are not included in medical records.

“All of these associational studies suffer from the fundamental problem that those who get vaccinated have different health habits than those who don’t,” says Dr. Pascal Geldsetzer, assistant professor of medicine and lead author of the new study. “It is generally considered that they do not provide strong enough evidence to make recommendations in this regard.”

But two years ago, Geldsetzer acknowledged a serendipitous “natural experiment” in the distribution of the shingles vaccine in Wales that seemed to circumvent the bias. The vaccine used at the time contained a live attenuated or weakened form of the virus. The vaccination program, which began on September 1, 2013, specified that anyone who was 79 years old on that date could be vaccinated for one year. (78-year-olds would be eligible the following year for one year, and so on.) Those who were 80 or older on September 1, 2013 were out of luck: They would never be eligible for the vaccine.

These rules, designed to ration the limited supply of the vaccine, also meant that the slight age difference between those aged 79 and 80 made a difference in who had access to the vaccine. By comparing people who turned 80 just before September 1, 2013 with those who turned 80 just after, the researchers were able to isolate the effect of being eligible for the vaccine.

WHY IS IT SUCH A POWERFUL STUDY?

The circumstances, well documented in the country’s health records, were as close to a randomized controlled trial as you can get without conducting one. In this way, the researchers analyzed the medical records of more than 280,000 older adults between 71 and 88 years old who did not suffer from dementia at the beginning of the vaccination program.

They focused their analysis on those who were closest to the eligibility threshold, comparing those who turned 80 the week before with those who turned 80 the week after.

“We know that if you take a thousand people born at random in one week and a thousand people born at random a week later, there should be no difference on average between them,” says Geldsetzer. “They are similar to each other, except for this small age difference.” It is likely that the same proportion of both groups would have wanted to receive the vaccine, but eligibility rules allowed only half – those not yet 80 years old.

“What makes the study so powerful is that it is essentially like a randomized trial with a control group (those who are slightly too old to be eligible for the vaccine) and an intervention group (those who are young enough to be eligible),” Geldsetzer argues.

A POSSIBLE WAY TO PREVENT—OR EVEN SLOW DOWN—DEMENTIA?”

Over the next seven years, researchers compared the health outcomes of people of similar age who met and they did not meet the requirements to receive the vaccine. By considering actual vaccination rates (about half of the eligible population received the vaccine, compared to almost none of the ineligible people), they were able to determine the effects of receiving the vaccine.

As expected, the vaccine reduced the incidence of shingles over that seven-year period by about 37% in people who received it, similar to what was seen in clinical trials of the vaccine. By 2020, one in eight older adults, who were then between 86 and 87 years old, had been diagnosed with dementia. However, those who received the shingles vaccine were 20% less likely to develop dementia than those who were not vaccinated.

The scientists exhaustively looked for other variables that might have influenced dementia risk, but found that the two groups were indistinguishable in all their characteristics. For example, no difference in educational level was observed between eligible and ineligible individuals. Those who were were not more likely to receive other vaccines or preventive treatments, nor were they less likely to be diagnosed with other common diseases, such as diabetes, heart disease and cancer.

The only difference was the drop in dementia diagnoses. “Because of the unique way the vaccine was rolled out, bias in the analysis is much less likely than would be typical,” Geldsetzer says.

However, his team analyzed the data in alternative ways (using different age ranges or looking only at deaths attributed to dementia, for example), but the link between vaccination and lower rates of dementia remained. When the researchers further analyzed health records, taking advantage of the same natural experiment, they found that the benefits of the vaccine extended from the first signs of cognitive decline to the later stages of dementia.

Many cases of dementia are preceded by a period of mild cognitive impairment, characterized by deficits in memory and cognitive skills that do not interfere with independent living, Geldsetzer says.

They found that people who received the vaccine were less likely to be diagnosed with mild cognitive impairment over a nine-year follow-up than those who were not vaccinated. Even more dramatic is that people who received the vaccine after a dementia diagnosis were significantly less likely to die from dementia in the following nine years (as indicated on their death certificates), suggesting that the vaccine could slow the progression of the disease.

Overall, almost half of the 7,049 older Welsh adults who had dementia at the start of the vaccination program died of dementia during follow-up, but only about 30% of those who received the vaccine died of dementia.

“The most exciting thing is that this really suggests that the shingles vaccine not only has preventive and dementia-slowing benefits, but also therapeutic potential for those who already suffer from it,” insists Geldsetzer.

In an additional finding, the study showed that protection against dementia was much more pronounced in women than in men. This could be due to gender differences in the immune response or in the way dementia develops, explains Geldsetzer. For example, women, on average, have a greater antibody response to vaccination, and shingles is more common in women than men.

It is still unknown whether the vaccine protects against dementia by boosting the immune system in general, specifically reducing reactivations of the virus, or through some other mechanism. It is also unknown whether a newer version of the vaccine, which contains only certain proteins of the virus and is more effective at preventing shingles, may have a similar or even greater impact on dementia.

Geldsetzer hopes the new findings will inspire more funding for this line of research. “At least investing some of our resources in investigating these pathways could lead to advances in terms of treatment and prevention,” he concludes.