Increased risk of dementia associated with herpes simplex virus infections: Evidence from a retrospective cohort study using U.S. electronic health records

Abstract

Background: Alzheimer's disease is the most common age-related dementia. Recent compelling evidence from previous retrospective electronic health record (EHRs) studies suggests that herpes simplex virus (HSV) infections may be a risk factor for developing dementia. However, no age and propensity score matched studies have been published in a United States general population cohort study to date.

Objective: We aimed to identify whether HSV infection shows a significantly increased risk of the development of dementia in a sizable and heterogeneous cohort. We investigated whether herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), or coinfections with both serotypes pose a greater risk of developing dementia across different biological sexes and racial groups.

Methods: EHRs from patients with a history of HSV or specific serotypes (HSV1 or HSV2) infection were selected for analysis. These records were compared to a propensity-matched control group and analyzed for hazard and odds ratios through TriNetX.

Results: There was a significant difference in dementia incidence in the HSV-infected group versus the control. Individuals with a history of HSV, HSV1, HSV2, and coinfection all showed a significant risk of developing dementia compared to controls. Males with HSV2 are at a higher risk of dementia outcome than females with HSV2.

Conclusions: While consistent with previous reports, these findings are the first to establish a higher risk of developing dementia in patients who have any HSV diagnosis using a nationwide, population-based matched cohort study in the United States.

Keywords: Alzheimer's disease; clinical outcomes; dementia; electronic health records; herpes simplex virus.

Figure 1.

Cohort selection. Flowchart depicting patient cohort selection indicating the number of patients within each cohort stratification.

Figure 2.

Timeline of study design. The timeline shows that propensity score matching occurred any time before the index event. The outcome of dementia was measured any time after one year past the first HSV diagnosis. One year after HSV diagnosis was considered to allow for enough time for the reactivation of the virus to occur.

Figure 3.

Odds ratio for dementia diagnosis associated with HSV infection. The odds ratio for dementia diagnosis in patients with history of any HSV infection (2.149, 95% CI: 1.843–2.507), a history of specific serotype either HSV1 (2.16, 95% CI: 1.757–2.656), or HSV2 (2.119, 95% CI: 1.524–2.946) or a coinfection of both serotypes (3.468, 95% CI: 2.297–5.234). Error bars represent the 95% confidence intervals for each odds ratio.

Figure 4.

Kaplan-Meier curves indicate a higher cumulative risk of dementia diagnosis associated with HSV serotype infections. Each panel represents a different analysis of dementia diagnosis risk following HSV infection compared to a propensity-matched control cohort with no HSV diagnosis. The solid lines represent estimated dementia risk and shaded areas indicate the 95% confidence intervals. (A) Shows the dementia diagnosis risk for a non-specific HSV infection diagnosis. (B) Illustrates the dementia risk for HSV1 diagnosis. (C) Depicts the dementia risk for HSV2 diagnosis. (D) Dementia risk for the coinfection diagnosis (combined HSV1 and HSV2).