RESUMEN
The varicella zoster virus, a neurotropic herpesvirus, has been hypothesized to play a role in the pathophysiology of dementia, such as through neuroinflammatory processes or intracerebral vasculopathy. Using unique natural experiments, our group has previously found that live-attenuated herpes zoster (HZ) vaccination reduced the incidence of new diagnoses of dementia in both Wales and Australia. To inform further research and ultimately clinical care, it is crucial to understand at which stage of the disease course of dementia the HZ vaccine has its effect. Representing the two opposing ends of the dementia disease course as it can be ascertained from electronic health record data, the aims of this study were twofold: to determine the effect of HZ vaccination on i) new diagnoses of mild cognitive impairment (MCI) among individuals without any record of cognitive impairment, and ii) deaths due to dementia among individuals living with dementia. Our approach took advantage of the fact that at the time of the start date (September 1 2013) of the HZ vaccination program in Wales, individuals who had their eightieth birthday just after this date were eligible for HZ vaccination for one year whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. This eligibility rule created comparison groups just on either side of the September 2 1933 date-of-birth eligibility threshold who differed in their age by merely a week but had a large difference in their probability of receiving HZ vaccination. The key strength of our study is that these comparison groups should be similar in their health characteristics and behaviors except for a minute difference in age. We used regression discontinuity analysis to estimate the difference in our outcomes between individuals born just on either side of the date-of-birth eligibility threshold for HZ vaccination. Our dataset consisted of detailed country-wide electronic health record data from primary care in Wales, linked to hospital records and death certificates. We restricted our dataset to individuals born between September 1 1925 and September 1 1942. Among our study cohort of 282,557 without any record of cognitive impairment at baseline, HZ vaccination eligibility and receipt reduced the incidence of a new MCI diagnosis by 1.5 (95% CI: 0.5 - 2.9, p=0.006) and 3.1 (95% CI: 1.0 - 6.2, p=0.007) percentage points over nine years, respectively. Similarly, among our study cohort of 14,350 individuals who were living with dementia at baseline, being eligible for and receiving HZ vaccination reduced deaths due to dementia by 8.5 (95% CI: 0.6 - 18.5, p=0.036) and 29.5 (95% CI: 0.6 - 62.9, p=0.046) percentage points over nine years, respectively. Except for dementia, HZ vaccination did not have an effect on any of the ten most common causes of morbidity and mortality among adults aged 70 years and older in Wales in either of our two study cohorts. The protective effects of HZ vaccination for both MCI and deaths due to dementia were larger among women than men. Our findings suggest that the live-attenuated HZ vaccine has benefits for the dementia disease process at both ends of the disease course of dementia.
RESUMEN
Background: The United Kingdom (UK) has used date of birth-based eligibility rules for live-attenuated herpes zoster (HZ) vaccination that have led to large differences in HZ vaccination coverage between individuals who differed in their age by merely a few days. Using this unique natural randomization, we have recently provided evidence from Welsh electronic health record data that HZ vaccination caused a reduction in new dementia diagnoses over a seven-year period. Based on this, we hypothesized that HZ vaccination may have slowed the dementia disease process more generally and, thus, already reduced deaths with dementia as their underlying cause even though the UK's HZ vaccination program commenced as recently as September 2013. Using country-wide death certificate data for England and Wales, this study, therefore, aimed to determine whether eligibility for HZ vaccination caused a reduction in deaths due to dementia over a nine-year follow-up period. Methods: Adults who had their 80th birthday shortly before September 1 2013 were ineligible for HZ vaccination in the UK's National Health Service and remained ineligible for life, whereas those who had their 80th birthday shortly after September 1 2013 (i.e., born on or after September 2 1933) were eligible for one year. Akin to a randomized trial, this date-of-birth threshold generated birth cohorts who are likely exchangeable in observed and unobserved characteristics except for a small difference in age and a large difference in HZ vaccination uptake. We used country-wide data from death certificates in England and Wales on underlying causes of death from September 1 2004 to August 31 2022 by ICD-10 code and month of birth. Our analysis compared the percentage of the population with a death due to dementia among the month-of-birth cohorts around the September 2 1933 eligibility threshold using a regression discontinuity design. The primary analyses used the maximal available follow-up period of nine years. Results: The study population included 5,077,426 adults born between September 1 1925 and August 31 1941 who were alive at the start of the HZ vaccination program. The month-of-birth cohorts around the September 2 1933 eligibility cutoff were well balanced in their occurrence of all-cause and cause-specific deaths (including deaths due to dementia) prior to the start of the vaccination program. We estimated that over a nine-year follow-up period, eligibility for HZ vaccination reduced the percentage of the population with a death due to dementia by 0.38 (95% CI: 0.08 to 0.68, p=0.012) percentage points, corresponding to a relative reduction of 4.8%. As in our prior analysis, this effect was stronger among women (-0.62 [95% CI: -1.06 to -0.19] percentage points, p=0.004) than among men (-0.11 [95% CI: -0.51 to 0.28] percentage points, p=0.574). The reduction in deaths due to dementia likely resulted in an increase in remaining life expectancy because we found that HZ vaccination eligibility reduced all-cause mortality but had no effect on deaths not due to dementia. An effect on deaths due to dementia at the September 2 date-of-birth eligibility threshold existed only since the year in which the HZ vaccination program was implemented. Conclusions: Our findings indicate that HZ vaccination improved cognitive function at a fairly advanced stage of the dementia disease process because most individuals whose underlying cause of death was dementia during our nine-year follow-up period were likely already living with dementia at the start of the HZ vaccination program. By using a different population, type of data, and outcome than our prior study in Welsh electronic health record data, this analysis adds to the evidence base that HZ vaccination slows, or potentially even prevents, the natural history of dementia.
RESUMEN
The root causes of dementia are still largely unclear, and the medical community lacks highly effective preventive and therapeutic pharmaceutical agents for dementia despite large investments into their development. There is growing interest in the question if infectious agents play a role in the development of dementia, with herpesviruses attracting particular attention. To provide causal as opposed to merely correlational evidence on this question, we take advantage of the fact that in Wales eligibility for the herpes zoster vaccine (Zostavax) for shingles prevention was determined based on an individual's exact date of birth. Those born before September 2 1933 were ineligible and remained ineligible for life, while those born on or after September 2 1933 were eligible to receive the vaccine. By using country-wide data on all vaccinations received, primary and secondary care encounters, death certificates, and patients' date of birth in weeks, we first show that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely one week too old to be eligible, to 47.2% among those who were just one week younger. Apart from this large difference in the probability of ever receiving the herpes zoster vaccine, there is no plausible reason why those born just one week prior to September 2 1933 should differ systematically from those born one week later. We demonstrate this empirically by showing that there were no systematic differences (e.g., in pre-existing conditions or uptake of other preventive interventions) between adults across the date-of-birth eligibility cutoff, and that there were no other interventions that used the exact same date-of-birth eligibility cutoff as was used for the herpes zoster vaccine program. This unique natural randomization, thus, allows for robust causal, rather than correlational, effect estimation. We first replicate the vaccine's known effect from clinical trials of reducing the occurrence of shingles. We then show that receiving the herpes zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of seven years by 3.5 percentage points (95% CI: 0.6 - 7.1, p=0.019), corresponding to a 19.9% relative reduction in the occurrence of dementia. Besides preventing shingles and dementia, the herpes zoster vaccine had no effects on any other common causes of morbidity and mortality. In exploratory analyses, we find that the protective effects from the vaccine for dementia are far stronger among women than men. Randomized trials are needed to determine the optimal population groups and time interval for administration of the herpes zoster vaccine to prevent or delay dementia, as well as to quantify the magnitude of the causal effect when more precise measures of cognition are used. Our findings strongly suggest an important role of the varicella zoster virus in the etiology of dementia.