APOE ε4 carrier status increases the long-term cognitive decline risk associated with herpes zoster

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMAug 19 2024

A recent study published in Alzheimer’s Research & Therapy examined the long-term subjective cognitive decline risk associated with Herpes zoster infections. It investigated whether the association varied based on apolipoprotein E e4 (APOE ε4) gene carrier status, immunocompromised conditions, and vaccination against herpes zoster.

Study: Herpes zoster and long-term risk of subjective cognitive decline. Image Credit: chemical industry/Shutterstock.com

Background

Cognitive decline related to age is becoming a substantial global health burden in this rapidly aging world population, and the efficient management of cognitive decline requires a thorough understanding of its risk factors. Studies indicate that herpesvirus infections can impact cognitive decline risk and contribute to dementia.

Commonly referred to as shingles, herpes zoster occurs when the neurotrophic varicella-zoster virus, which causes chickenpox, gets reactivated.

Varicella-zoster virus contains double-stranded deoxyribonucleic acid (DNA) as its genetic material and, after the initial infection, remains in the ganglionic neurons in a latent stage in over 95% of the infected individuals. The reactivation of the virus in the ganglia and its spread to dermatomes causes herpes zoster.

The neuroinflammation, neuronal damage, and cerebral vasculopathy that occur with herpes zoster are believed to increase the risk of dementia. Some studies have also associated herpes zoster with an increased risk of Alzheimer's disease.

At the same time, infections with herpes simplex virus have also been linked to episodic memory decline and higher Alzheimer's disease risk.

About the study

In the present study, the researchers examined the longitudinal association between herpes zoster and subjective cognitive decline risk using three well-characterized, large cohorts of male and female participants.

They also investigated whether this association was modified by APOE ε4 status, immunocompromised conditions, or herpes zoster vaccination status.

The three cohorts were from the Nurses’ Health Studies I and II, and the Health Professionals Follow-Up Study. The ascertainment of herpes zoster infections was based on data collected for multiple years between 2000 and 2017. Self-reported herpes zoster infections were validated using medical records.

Subjective cognitive decline assessments were conducted for multiple years for each of the three cohorts using six questions with a yes or no answer. These questions determined whether the participants had trouble remembering lists, directions, storylines of television series, recent events, etc. The assessment also examined any recent changes in memory capacity.

Data on various covariates were collected at baseline and during follow-ups. These included demographic factors such as age, sex, and race and lifestyle factors such as alcohol consumption, smoking, physical activity levels, and dietary quality.

Other covariates included information on the family history of dementia, body mass index, hypertension, diabetes, coronary heart disease, cholesterol levels, depression, and a wide range of diseases such as cancer, Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma, and ulcerative colitis which required the use of immunosuppressants or steroids.

Some covariate data was specific for each sex. Menopausal status and menopausal hormone therapy are considered only for women, along with the husband’s education levels and annual income. For the male participants, the analysis was further adjusted for professions associated with the medical field.

Results

The findings confirmed that herpes zoster infection was associated with an increase in the long-term risk of subjective cognitive decline.

Furthermore, this association differed based on whether the individual carried the APOE ε4 risk factor for Alzheimer's disease.

Herpes zoster was associated with a 20% increase in the long-term risk of subjective cognitive decline. Among men, APOE ε4 carriers had a significantly higher risk of cognitive decline than men who were not carriers of the Alzheimer's risk factor, but the same pattern was not observed in women.

Immunocompromised status did not seem to have an impact on the association between herpes zoster and cognitive decline, but the lack of vaccination against herpes zoster was believed to increase the risk of cognitive decline significantly.

Some of the potential mechanisms through which herpes zoster contributes to cognitive decline were discussed in the study.

Neuroinflammation due to the virus is believed to cause neuronal damage, resulting in cognitive decline. Other potential mechanisms include cerebrovascular pathologies such as vasculopathy and the activation of herpes simplex virus-1.

Vasculopathy can result in vasculature remodelling, increasing the risk of ischemia and vascular occlusion. Varicella-zoster virus is also thought to increase the amyloid burden and accelerate the progression of Alzheimer's disease.

Conclusions

The results showed that herpes zoster increased the risk of subjective cognitive decline. The association between herpes zoster and cognitive decline was modified based on APOE ε4 carrier status but not by immunocompromised status. Vaccination against herpes zoster was found to decrease the risk of cognitive decline.