Antiviral Treatment of Herpes Simplex Virus Decreases the Risk of Alzheimer’s Disease and Dementia

March 2026 | Volume 25 | Issue 3 | 234 | Copyright © March 2026


Published online February 26, 2026

Margaret Kabakova BSa,b*, Paras Patel BAa,c*, David Bitterman BAa,d*, Jennifer Y. Wang BAa,b*, Kayla Zafar BAa,e, Dustin A. Fife PhDf, Marc Cohen MDa,b, Alana Kurtti MDa,b, Jared Jagdeo MD MSa,b

aDermatology Service, Veterans Affairs New York Harbor Healthcare System – Brooklyn Campus, Brooklyn, NY
bDepartment of Dermatology, State University of New York, Downstate Health Sciences University, Brooklyn, NY
cRowan University School of Osteopathic Medicine, Stratford, NJ
dNew York Medical College, Valhalla, NY
eSt. George's University School of Medicine, Grenada, West Indies
fRowan University College of Science and Mathematics, Glassboro, NJ

Abstract
Background: Alzheimer's disease (AD) and dementia create major global health and economic burdens. Herpes simplex virus (HSV) infects over 3 billion people, and chronic infection is increasingly linked to neurodegeneration.
Objectives: To evaluate whether antiviral therapy for oral, mucocutaneous, or anogenital HSV lowers the subsequent risk of AD and dementia.
Methods: A retrospective cohort study with propensity-score matching was performed in the TriNetX Research Network. On 24 May 2024, 615,324 individuals with HSV were identified; those with prior AD, intracranial injury, or cerebral infarction were excluded. Matching balanced age, sex, race, body-mass index, smoking, diabetes, and hypertension between antiviral-treated and untreated groups. Therapies included acyclovir, valacyclovir, penciclovir, ganciclovir, valganciclovir, and famciclovir. Incidences of AD and dementia were identified by ICD-10 codes, and relative risks (RR) with 95% confidence intervals (CI) were calculated.
Results: After matching, 231,277 patients per cohort (mean age 36.8 y; 67.7% female) were analyzed. Antiviral treatment for oral/mucocutaneous HSV significantly reduced the risk of AD (RR 0.87; 95% CI 0.73-0.92) and dementia (RR 0.83; 95% CI 0.77-0.90). No significant association was observed for anogenital HSV.
Conclusions: Antiviral therapy for oral or mucocutaneous HSV was associated with a 13% to 17% reduction in risk for AD and dementia. These findings suggest that early antiviral management of HSV infections may represent a feasible preventive strategy against neurodegenerative disease, meriting prospective confirmation.

 

INTRODUCTION

Herpes simplex virus (HSV), responsible for oral and genital herpes, impacts over 3 billion people worldwide.1 HSV-1 typically causes oral herpes, while HSV-2 usually leads to genital herpes, though either virus can infect both anatomical sites.1-5 HSV lesions are often self-limiting, and thus antiviral treatment is not routinely prescribed for all cases.6 Furthermore, HSV may not always cause apparent mucocutaneous lesions and may appear to be dormant in the trigeminal sensory ganglion.6 HSV-2 is associated with a 3-fold increased risk of contracting human immunodeficiency virus (HIV) infection.7 About one-third of Americans have recurrent labial herpes (1-6 outbreaks/year).8,9 Under current guidelines, patients experiencing severe and frequent HSV outbreaks (>6 per year) may receive antiviral therapy for treatment and prophylaxis.9

Alzheimer's disease (AD) is a progressive debilitating neurologic disorder characterized by impaired behavior and cognition.10 In 2023, the prevalence of AD was 6.7 million in the US and is projected to increase to 13.8 million by 2060.11 Known risk factors for AD include cardiovascular disease, obesity, cigarette smoking, and diabetes mellitus.12 Over $345 billion USD was spent on AD and dementia treatment in 2022, and this cost is estimated to increase to over $1 trillion by 2050.11,13 As of 2024, the US federal government is investing $3.8 billion USD on AD and dementia research, highlighting the urgent need for new insights and interventions.14

The risk of developing AD increases by 1.5 to 3.5 times in individuals with a history of HSV;6 notably, prior studies observed lower AD prevalence in HSV-infected patients treated with antivirals vs untreated cohorts.15-17 Supporting