In this study, cognitive decline was more pronounced in HSV1 seropositive compared to seronegative participants in global cognition and the cognitive domains of memory, information processing and executive function13. There was no association between HSV1 and the development of dementia.
The current literature mainly focuses on the final stage of deteriorated cognition: dementia6 and only few studies have investigated cognition12,13. In the studies that found an association between declined cognition and HSV, it was only with high infectious burden, i.e. multiple viruses (a combination of HSV1, HSV2, and Cytomegalovirus)14 or in carriers of APOE-ε415. One study found no association between HSV1 and cognitive decline 16.
Previous studies found conflicting results regarding the association between HSV1 and dementia6. Two previous cohort studies varied from our cohort in having a shorter follow-up time (the longest being 4 years), which makes these studies more prone to reverse causation17,18,. In a Taiwanese retrospective cohort study they found an association, but all the HSV cases included in the study were more virulent infections requiring anti-viral medication which may have resulted in stronger effects19. Another study only saw the association in APOE-ε4 carriers20, unlike our study. In one of the few longitudinal studies on the subject, an association was found only with HSV1 immunoglobulin M (IgM) antibodies and AD but not with HSV1 IgG antibodies and AD (HR: 0.99, 95% CI: 0.57; 1.72)21 which is consistent with our study. Another study looking at HSV IgG antibodies and dementia revealed a HR of 1.67 (95% CI: 0.75; 3.73)22, yet both of these studies failed to differentiate between HSV1 and HSV2 antibodies. A third prospective cohort study studying the same association found a HR of 0.77 (95% CI: 0.58; 1.04) for HSV1 specific IgG antibodies23. It is possible that the presence of HSV1 IgG antibodies does not lead to constant inflammation; therefore, the latent virus is not associated with greater cognitive disturbances. Since our study comprised the general population, a high prevalence of latent HSV1 was expected as opposed to a reactivated infection.
A potential mechanism for an HSV1 infection to affect cognition is via a temporary production of amyloid beta to repress the infection. This leads to short-lived inflammation which affects cognition according to the recent antimicrobial protection hypothesis of AD1. Once the infection and subsequent inflammation are gone, cognition is no longer impaired.
In our study, the HSV1 infection as measured by IgG antibodies (latent infection) are associated with a subtle decrease in global cognition over time. Due to lack of information on cognition tests at later examination dates (after 2011) in our study, we do not know whether cognition stayed at the new decreased level or if it returned to the previous level measured at baseline. However, our results suggest that it did not decrease further; otherwise, we would have observed an association between HSV1 and dementia. The combination of multiple neurotoxic viruses may be required to cause permanent damage to cognitive function, therefore HSV1 alone is not enough to see a significant effect.
A major strength of this study was the availability of prospectively collected data and the length of follow-up time. In addition, we were able to analyze both the subtle (i.e. cognition) and large changes in cognition (i.e. dementia) in one study.
It is also important to consider the limitations of this study. A major one is the availability of only HSV1 IgG antibodies which only gave us information on infection prior to baseline. Without data on the HSV1 IgM, we were unable to tell whether the participants had an active HSV1 infection at baseline. Since the reactivation of the virus is the proposed pathway to deteriorating cognition, we would need to investigate HSV1 IgM antibodies and each stage of deteriorating cognition to gain a better understanding. Another limitation is the lack of generalizability as the Rotterdam Study cohort predominantly consists of Caucasian participants living in a middle-income area in Rotterdam.
In conclusion, HSV1 is associated with a decrease in global cognition and cognitive domains, but not with dementia risk in the general population. These findings suggest that HSV1 IgG antibodies may lead to subtle cognitive disturbances but not greater cognitive disorders.