Herpes Simplex Virus, APOE ε4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study

Background: Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer's disease (AD) development. Objective: The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOE epsilon 4) in a large population-based cohort with a long follow-up time. Methods: The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOE epsilon 4 carriage, and episodic memory was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared. Results: Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOE epsilon 4 carriers (p = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (>= 65 years: p < 0.001, all ages: non-significant), and a significant interaction between HSV and APOE epsilon 4 for episodic memory decline (p < 0.001). Conclusion: In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOE epsilon 4 carriers. The results strengthen the hypothesis that HSV is associated with AD development.