Receipt of the shingles vaccine Zostavax may offer protective benefits against mild cognitive impairment (MCI) in cognitively healthy older adults and significantly slow disease progression in those diagnosed with dementia before vaccination, a new study showed.

After 9 years of follow-up, dementia-related mortality was 30% lower among vaccinated individuals with preexisting dementia than among unvaccinated individuals, which investigators said suggests a link with slower disease progression.

All observed protective events were strongest in women and dementia-related mortality was lowest among those with more advanced disease at the time of vaccination.

The study builds on earlier work that showed a link between the shingles vaccine and lower dementia risk and takes advantage of a unique opportunity to compare vaccinated and unvaccinated groups that differed only by slightly different ages. This fortifies the findings compared to previous observational studies that only found an association, researchers said.

“For the first time, we now have evidence that is much more likely to reflect true cause and effect…that shingles vaccination has benefits for dementia prevention and potentially treatment,” senior investigator Pascal Geldsetzer, MD, PhD, MPH, assistant professor of medicine in the Division of Primary Care and Population Health and, by courtesy, in the Department of Epidemiology and Population Health at Stanford University in Stanford, California, told Medscape Medical News.

The study was published online on December 2 in the journal Cell.

An Unanswered Question

Because neuroinflammation plays a central role in both the onset and progression of dementia, neurotropic viruses such as the varicella zoster virus could contribute to or accelerate the underlying disease process, researchers noted.

In a study published in Nature earlier this year and covered by Medscape Medical News, Geldsetzer and colleagues reported that receiving a live attenuated herpes zoster vaccination was associated with a reduction in dementia diagnosis by a relative risk of 20% over a follow-up of 7 years among individuals in Wales. They later confirmed their findings in a similar cohort in Australia.

However, it was unknown if the strength of the vaccine’s protective benefits against dementia varied based on disease stage.

To explore that question, researchers again utilized a dataset from Wales, where eligibility for Zostavax vaccination is dependent on an individual’s date of birth. The new research included 282,557 residents born between September 1, 1925, and September 1, 1942, who had no dementia diagnosis prior to September 2013 when Wales launched its vaccination program.

Because of limited supplies, health officials limited eligibility in the first year to people aged 79 years. Those aged 78 years or younger had to wait for vaccination, and those aged 80 years or older were ineligible.

Study data came from electronic health record information from about 80% of the country’s primary care practices in the Secure Anonymized Information Linkage databank.

To assess any effect on dementia-related deaths associated with vaccination, the researchers also evaluated 14,350 Wales residents diagnosed with dementia before September 2013.

To keep the groups as similar as possible, the researchers compared people right before and after the September 2, 1933, birth date cutoff for eligibility.

“We see in our data that just a 1-week difference across this date-of-birth cutoff means that you go from essentially no one getting vaccinated to about half (46%) of the population getting vaccinated,” Geldsetzer said.

Effects ‘Large in Magnitude’

Of the people with no record of cognitive impairment at baseline, 7.3% were diagnosed with MCI during the 9-year follow-up. Nearly half (49.1%) of those with a preexisting dementia diagnosis died from the disease during the study period.

Herpes zoster vaccination was associated with a 3.1-percentage-point reduction in new MCI diagnosis in the overall cohort (95% CI, 1.0-6.2; P = .007) and a 5.1-percentage-point decrease in women (95% CI, 2.6-9.8; P < .001).

Dementia-related mortality was also lower in vaccinated individuals with a prior dementia diagnosis. In the overall cohort, vaccination was associated with a 29.5-percentage-point reduction in mortality (95% CI, 0.6-62.9; P = .046) and a 52.3-percentage-point decrease in women (95% CI, 9.2-97.9; P = .018).

“Although none of our results were statistically significant among men, we cannot exclude the possibility of substantial beneficial effects among men as well, given the width of our confidence intervals,” the investigators noted.

Asked if he was surprised by the magnitude of the protective effects of vaccination in the study, Geldsetzer said, “Yes, the effects we are seeing are large in magnitude, certainly much larger than for existing pharmacological tools for dementia.”

It is “particularly exciting,” Geldsetzer added, “that we see the same protective effect from shingles vaccination for dementia in dataset after dataset — in different populations and different countries that rolled out the vaccine in a similar way as Wales did.”

Given the older age of the study population, it is unclear if the benefits would be found in younger individuals. In addition, data in the study came from electronic health record and death record databases.

Geldsetzer said a clinical trial is needed to confirm the current study findings and the mechanisms behind the vaccine’s protective effects.

Zostavax (Merck) was approved by the FDA in 2006 and is no longer available in the US as of 2020. It is unknown if the newer Shingrix nonlive, recombinant zoster vaccine approved in 2017 will confer the same MCI and dementia protections, investigators said.

More Research Warranted

Commenting for Medscape Medical News, Courtney M. Kloske, PhD, director of scientific engagement, Alzheimer’s Association, Chicago, noted that the findings are consistent with previous studies and echoed the call for larger studies.

“More rigorous data is needed to properly inform public health strategy about the potential role or roles of vaccinations in reducing risk of developing dementia as we age,” said Kloske, who was not involved in the study.

Kloske added further research could also confirm the greater protective effects in women and any examine why there is a sex difference.

“There are a number of potential biological and social factors involved in why women have a higher risk than men for Alzheimer’s or other diseases that cause dementia. The prevailing view has been that this discrepancy is due to women living longer than men on average,” Kloske said. “However, researchers are now questioning whether Alzheimer’s risk could be higher for women at any given age due to biological or genetic variations or differences in life experiences.”

Also commenting for Medscape Medical News, Shaheen Lakhan, MD, PhD, a neurologist practicing in Miami, said, “The stronger protective effect in women is striking, but it aligns with what we know about both immune and brain aging.”

Women tend to mount more robust responses to live-attenuated vaccines, and they experience shingles reactivation more often in older age, noted Lakhan, who was not part of the research.

“Preventing these reactivations may reduce neuroinflammation, which could explain the amplified benefit. One underappreciated point is that women don’t just respond differently to vaccines, they also develop dementia differently — the immune system and the brain age differently in women, and this study seems to capture that intersection in real time,” Lakhan added.

If validated, the idea that the shingles vaccine could slow dementia progression is one of the most important aspects of this study, he noted.

“We have very few tools that benefit people after dementia has begun. It is far too early to treat this as a therapy, but it opens the door to inexpensive, scalable interventions and justifies urgent randomized trials,” Lakhan said.

The study was funded by grants to Geldsetzer by The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University; the National Institute on Aging; National Institute of Allergy and Infectious Diseases; and the Chan Zuckerberg Biohub San Francisco. Geldsetzer, Kloske, and Lakhan reported having no relevant financial relationships.