A large prospective cohort study found that herpes zoster infection was associated with a higher long-term risk of subjective cognitive decline in both men and women.
The study, published in Alzheimer's Research & Therapy, analyzed data from 149,327 participants across three cohorts. Researchers from Harvard T.H. Chan School of Public Health and affiliated institutions examined data from the Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-Up Study (HPFS). The study included 56,142 women from the NHS (mean age = 64.6 years), 66,966 women from the NHS II (mean age = 47.2 years), and 26,219 men from the HPFS (mean age = 68.5 years).
Key Findings
In the NHS, herpes zoster (HZ) infection was associated with higher long-term risk of subjective cognitive decline (SCD), with a multivariable-adjusted relative risk (MVRR) of 1.14 (95% confidence interval [CI] = 1.01-1.32) for ≥13 years since HZ occurrence. In the NHS II, HZ was associated with higher risk of SCD in both short-term (MVRR = 1.34; 95% CI = 1.18-1.53 for 1-4 years) and long-term (MVRR = 1.20; 95% CI = 1.08-1.34 for ≥13 years) follow-up. In the HPFS, an elevated risk of SCD was suggested across all time points following HZ, with MVRRs ranging from 1.21 to 1.42.
The association between HZ and SCD risk differed by APOE ε4 carrier status, particularly among men. Male APOE ε4 carriers showed a significantly higher risk (MVRR = 1.81; 95% CI = 1.10-2.98 for ≥5 years since HZ; p-interaction = 0.02), while results were inconsistent for women. The association did not significantly differ among individuals with and without potentially immunocompromising conditions.
Data from NHS II suggested that the long-term risk of SCD may be greater among women who were not vaccinated against HZ (MVRR = 1.28; 95% CI = 1.13-1.45 for ≥5 years since HZ) compared to those who were vaccinated (MVRR = 1.09; 95% CI = 0.90-1.32; p-interaction = 0.09).
Methods
The study used Poisson regression to estimate the MVRR of a 3-unit increment in SCD score according to years since HZ infection compared with participants with no history of HZ. SCD was assessed using a validated questionnaire consisting of six to seven yes/no questions about cognitive function.
Researchers adjusted for numerous confounding factors, including age, race, family history of dementia, smoking, alcohol consumption, body mass index, physical activity, diabetes, hypertension, elevated cholesterol, stroke, coronary heart disease, dietary quality, depression, and immunocompromising conditions.
The validity of self-reported HZ infection was confirmed through a validation study comparing questionnaire reports with medical records, showing 99.6% accuracy (230 out of 231 cases confirmed).
Additional Data
The prevalence of HZ in the cohorts was 14.2% in the NHS, 14.0% in the NHS II, and 9.5% in the HPFS.
Detailed risk ratios for different time periods since HZ occurrence were reported:
NHS:
- 1 to 4 years since HZ: MVRR = 1.08 (95% CI = 0.94-1.24)
- 5 to 8 years since HZ: MVRR = 0.92 (95% CI = 0.82-1.03)
- 9 to 12 years since HZ: MVRR = 1.04 (95% CI = 0.92-1.17)
- ≥13 years since HZ: MVRR = 1.14 (95% CI = 1.01-1.32).
NHS II:
- 1 to 4 years since HZ: MVRR = 1.34 (95% CI = 1.18-1.53)
- 5 to 8 years since HZ: MVRR = 1.05 (95% CI = 0.93-1.19)
- 9 to 12 years since HZ: MVRR = 1.05 (95% CI = 0.89-1.24)
- ≥13 years since HZ: MVRR = 1.20 (95% CI = 1.08-1.34).
HPFS:
- 1 to 4 years since HZ: MVRR = 1.21 (95% CI = 0.97-1.53)
- 5 to 8 years since HZ: MVRR = 1.38 (95% CI = 1.04-1.84)
- 9 to 12 years since HZ: MVRR = 1.42 (95% CI = 1.04-1.92)
- ≥13 years since HZ: MVRR = 1.24 (95% CI = 0.97-1.58).
Stratification by immunocompromised status showed similar trends in all three cohorts, with no significant differences between immunocompromised and nonimmunocompromised individuals.
The authors noted several limitations, including the observational nature of the study, potential residual confounding, and the predominantly White, highly educated cohort, which may limit generalizability.
They concluded, "Data from three large independent cohorts of women and men showed that HZ was associated with higher long-term risk of SCD, and the risk may differ by APOE ε4-carrier status."
Ethics declarations are available in the study.