The herpes virus infection is linked to a higher risk of Alzheimer's disease, the study shows that antiherpetic drugs may help

The herpes virus infection is linked to a higher risk of Alzheimer's disease, the study shows that antiherpetic drugs may help

New research using U.S. insurance data finds that people with HSV-1 are more likely to develop Alzheimer's disease and may suggest antiviral drugs can reduce that risk.

Large American real-world data (RWD) provides further evidence of an association between herpes simplex virus type 1 (HSV-1) infection and the development of Alzheimer's disease (AD) and suggests the potential of using antiherpetic therapies as potentially protective against AD and related dementias.

A current oneBMJ openThe study from the United States examined the association between HSV-1 and AD using RWD.

Alzheimer's disease and herpes viruses

AD is a chronic and progressive neurodegenerative disease that affects an individual's thinking, reasoning and memory. Nearly 60%–80% of individuals with AD develop dementia, resulting in long-term healthcare burdens. Currently, around 35.6 million people have been diagnosed with dementia worldwide and the rapid increase is attributed to an aging population. To combat the increasing 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-neurofibrillar tangles and central nervous system amyloid-β (Aβ) plaques of 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 occurs predominantly in the global population between 0 and 49 years of age. Most children who contract this infection may remain asymptomatic. HSV-1 establishes latency in the trigeminal ganglia and exhibits periodic symptomatic reactivations, causing ocular disease, oral ulceration, and rarely meningoencephalitis.

A mouse model study showed that HSV-1 infection leads to Aβ deposition and other AD-related changes. Furthermore, experimental reactivation of HSV-1 infection caused changes in pathological hallmarks in a dose-responsive manner. Several real-world studies have shown that patients diagnosed with HSV-1 and other related neurotropic viruses are at 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 the US real-world nationwide 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 inpatient and outpatient data and drug prescriptions administered were obtained from IQVIA PharmaTrics Plus, the largest commercial claims database in the United States, covering more than 215 million candidates since 2006. Since the study is based on administrative claims. This means that the proportion of HSV-1 diagnoses recorded in this study is much lower than the actual prevalence in the general population, which is estimated to be around two-thirds for those under 50 years of age worldwide. Additionally, people over 65 years of age are underrepresented in this dataset.

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

Study results

The current study identified 395,654 patients with AD, of whom 344,628 met the eligibility criteria. These candidates were matched with the controls. Most of the AD group were women with an average age of 73 years. AD patients belong to a large, evenly distributed geographical area.

Most patients with AD had more comorbidities and shorter follow-up times compared to those in the control group. The current study found that 1,507 (0.44%) patients with AD also had an HSV-1 diagnosis compared to 823 (0.24%) controls.

Conditional logistic regression analysis revealed that HSV-1 diagnosis was associated with AD with an adjusted odds ratio (OR) of 1.80. Stratified analysis showed that this association was increasingly prominent in older age groups. Similar observations were also documented in the ADRD study population. Specifically, this study found an association between HSV-2 and VZV with AD, similar to HSV-1, while no significant difference was observed for CMV.

A subgroup analysis showed that 40% of 2,330 patients with a history of HSV-1 who received antiherpetic medications had a lower relative risk of developing AD (adjusted HR 0.83, 95% CI 0.74 to 0.92) compared to individuals who did not use antiherpetics. It is important to note that this hazard ratio reflects a relative risk reduction within the group of people diagnosed with HSV-1 and not in the general population. However, this observed association does not indicate that antiherpetic medications prevent Alzheimer's disease. Further studies are needed to determine whether a causal relationship exists.

Diploma

The current study provides further evidence of an association between symptomatic HSV-1 infection and AD using large-scale, real-world data. 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 association, not causation, and several limitations, including underdiagnosis of HSV-1 and Alzheimer's disease, potential misclassification, and underrepresentation of older adults—should be noted. The results also suggest that the neurodegenerative impact of HSV-1 becomes more evident with advancing age and cumulative exposure. Further research is needed in the future to clarify whether suppression of neurotropic viruses can alter the natural history of AD and ADRD.

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