Herpes virus infection linked to higher Alzheimer’s risk, study shows antiherpetic drugs may help

By Dr. Priyom Bose, Ph.D.May 21 2025

New research using US insurance data finds that people with HSV-1 face greater odds of Alzheimer’s disease, and suggests antiviral medications could help lower that risk.

Study: Association between herpes simplex virus type 1 and the risk of Alzheimer’s disease: a retrospective case–control study. Image Credit: Kateryna Kon / Shutterstock

Large-scale American real-world data (RWD) provides further evidence for an association between herpes simplex virus type 1 (HSV-1) infection and the development of Alzheimer’s disease (AD) and points out the potential of using antiherpetic therapies as possibly protective against AD and related dementia.

A recent BMJ Open study from the United States investigated the association between HSV-1 and AD using RWD.

Alzheimer’s disease and herpesviruses

AD is a chronic and progressive neurodegenerative disease that affects an individual’s thinking, reasoning, and memory. Almost 60%–80 % of individuals with AD develop dementia, which causes long-term healthcare burdens. At present, approximately 35.6 million people worldwide have been diagnosed with dementia, and the rapid increase is attributed to an aging population. To combat the rising incidence of AD worldwide, there is an urgent need for effective interventions.

Individuals with AD and related dementia develop a characteristic toxic protein aggregate, with τ neurofibrillary tangles and central nervous system amyloid-β (Aβ) plaques being pathological hallmarks. A previous study revealed the role of exogenous pathogens, particularly HSV-1, in AD development.

HSV-1 is a common viral infection that predominantly occurs in the global population between 0 and 49 years of age. Most children contracting this infection may remain asymptomatic. HSV-1 establishes latency in the trigeminal ganglia and exhibits periodic symptomatic reactivations, causing ocular disease, oral ulcerations, and rarely meningoencephalitis.

A mouse model study indicated that HSV-1 infection leads to Aβ deposition and other AD-related alterations. Furthermore, experimental reactivation of HSV-1 infection caused alterations in the pathological hallmarks in a dose-responsive fashion. Several real-world studies have shown that patients diagnosed with HSV-1 and other related neurotropic viruses are at a higher risk of developing dementia. Interestingly, studies conducted in Taiwan, Sweden, and France demonstrated protective effects of antiherpetics against dementia.

Scientists have indicated the need for a large-scale study based on real-world data to validate the role of HSV-1 in AD development and the therapeutic effects of antiherpetics against dementia.

About the study

The current retrospective matched case-control study used US-based nationwide real-world data to demonstrate the association between HSV-1 and AD and AD-related dementia (ADRD), including Pick’s disease, Lewy bodies, frontotemporal dementia, vascular dementia, and unspecified dementia.

All relevant data regarding inpatients and outpatients and prescriptions of administered drugs were obtained from IQVIA PharMetrics Plus, the largest commercial claims database in the USA, comprising more than 215 million candidates since 2006. Because the study relies on administrative claims data, it likely underestimates the true prevalence of HSV-1, which is often asymptomatic and may not be diagnosed or recorded. This means that the proportion of HSV-1 diagnoses captured in this study is much lower than the actual prevalence in the general population, which globally is estimated at around two-thirds for those under 50 years old. Additionally, individuals over 65 years are underrepresented in this dataset.

Cases with AD or ADRD were matched to those without a history of neurological disorders (control) in a 1:1 ratio on sex, age, region, database entry year, and inpatient and outpatient healthcare visit numbers. Two sets of matching and analyses were performed. The index date for the cases was the date when patients were diagnosed with AD/ADRD for the first time between 1 January 2006 and 30 June 2021. For the matched controls, all candidates were required to be 50 years or older at the index date. Individuals diagnosed with HSV-1 and other herpesviruses, such as HSV-2 and cytomegalovirus (CMV), before the index date were recorded.

Study findings

The current study identified 395,654 patients with AD, of whom 344,628 fulfilled the eligibility criteria. These candidates were matched to controls. Most of the AD group were females, with a mean age of 73 years. AD patients belong to a large, evenly distributed geographic area.

Most patients with AD had more comorbidities and shorter follow-up times compared with the individuals in the control group. The current study observed that 1,507 (0.44%) patients with AD also had a history of HSV-1 diagnosis, compared to 823 (0.24%) control subjects.

Conditional logistic regression analysis revealed that HSV-1 diagnosis was associated with AD with an adjusted odds ratio (OR) of 1.80. A stratified analysis demonstrated this association was increasingly prominent in older age groups. Similar observations have been documented in the ADRD study population as well. This study particularly found an association between HSV-2 and VZV with AD, similar to HSV-1, while no significant difference was observed for CMV.

A subset analysis demonstrated that 40% of 2,330 patients with a history of HSV-1 who received antiherpetic medications were at a lower relative risk of developing AD (adjusted HR 0.83, 95% CI 0.74 to 0.92) compared with those who did not use antiherpetics. It is important to note that this hazard ratio reflects a relative risk reduction within the group of individuals diagnosed with HSV-1, rather than in the general population. However, this observed association does not establish that antiherpetic medication prevents Alzheimer’s disease; further studies are needed to determine if a causal relationship exists.

Conclusion

The current study provides further evidence for an association between symptomatic HSV-1 infection and AD using large-scale real-world data. Most importantly, it highlights that antiherpetic therapies were associated with a reduced risk of AD in individuals diagnosed with HSV-1. However, this study can only establish an association, not causation, and several limitations, including underdiagnosis of HSV-1 and Alzheimer’s disease, potential misclassification, and under-representation of older adults—should be noted. The findings also suggest that the neurodegenerative impact of HSV-1 becomes more apparent with advancing age and cumulative exposure. In the future, more research is required to elucidate whether suppression of neurotropic viruses can modify the natural history of AD and ADRD.