Association of Herpes Simplex Virus Type-1 With Dementia Outcomes: A Longitudinal Retrospective Cohort Study Using Real World EHR Data (Preprint)

<sec> <title>BACKGROUND</title> Global dementia cases, currently exceeding 55 million, are projected to triple by 2050. In the absence of disease-modifying therapies, identifying modifiable risk factors is critical to mitigating this impending crisis. Preclinical studies have demonstrated that herpes simplex virus type-1 (HSV-1) exhibits neurotropism and can invade the central nervous system and drive pathological processes such as amyloid-beta accumulation and tau hyperphosphorylation, supporting the hypothesis that HSV-1 contributes to neurodegenerative processes. Epidemiologic findings are inconsistent, partly because many studies lack standardized designs for real-world data (RWD). </sec> <sec> <title>OBJECTIVE</title> To quantify the association between clinically coded HSV-1 infection and diagnosis of cognitive impairment or dementia among patients receiving care in a health-system electronic health record (EHR) network. </sec> <sec> <title>METHODS</title> We assembled a retrospective cohort within an OMOP-mapped EHR data lake (2010-2024), comparing patients with a first HSV-1 diagnosis (n = 6,274) to those without HSV-1 codes but with parallel baseline criteria (n = 379,975). Eligibility required ≥365 days of prior observation and absence of baseline cognitive, HIV, selected neurotropic viral, or recent transplant codes. The outcome combined mild cognitive impairment and Alzheimer disease-related dementias. A high-dimensional propensity score incorporating ~17 000 baseline covariates was estimated with regularized logistic regression; four strata weights were applied in a Cox model. Sensitivity analyses examined equipoise trimming, doubly adjusted models, fixed 1, 5, and 10-year censoring horizons, and a dementia-only outcome subset. Negative-control outcomes (n = 271) were analyzed for empirical calibration. </sec> <sec> <title>RESULTS</title> The HSV-1 cohort contributed 23,186 person-years (PY) and 469 events; the non-HSV-1 cohort contributed 1,519,828 PY and 24,764 events. The crude incidence rate was 20.23 (95% CI 18.44-22.14) per 1,000 person-years in the HSV-1 cohort compared to 16.29 (95% CI 16.09-16.50) in controls, yielding an absolute difference of 3.94 events per 1,000 person-years. Propensity-score-stratified analysis yielded a hazard ratio (HR) of 1.14 (95 % CI 1.03-1.25, P=.01). Estimates were comparable after equipoise trimming (HR 1.12, 95 % CI 1.01-1.25, P=.037), doubly adjusted modeling (HR 1.13, 95 % CI 1.02-1.24, P=.014), and fixed 5 year (P=.008) and 10-year follow-up (P=.004) (both HR 1.15). The 1-year censored model showed HR 1.00 (95 % CI 0.84-1.20, P=1). Results for the dementia-only endpoint mirrored the primary analysis (HR 1.14, 95 % CI 1.03-1.25, P=.008). Negative-control calibration was not performed due to zero events. </sec> <sec> <title>CONCLUSIONS</title> Within an OMOP-standardized EHR cohort, an HSV-1 diagnosis was associated with a small elevation in the hazard of subsequent cognitive impairment or dementia. Given the ubiquity of HSV-1 infection, even a modest increase in dementia risk may translate to substantial additional cases at the population level. Confirmation in external data sets that include laboratory viral typing, antiviral treatment records, and mortality linkage is warranted. </sec>