A growing body of literature is associated with the debate over whether persistent viral infection provides a significant contribution to Alzheimer’s disease and other neurodegenerative conditions. Some viruses, such as varieties of herpes simplex virus (HSV), cannot be effectively cleared by the immune system. They linger in the body to continually provoke immune reactions. The contribution of viral infection is clearly not reliable and sizable, however, as the epidemiological evidence is mixed. Some study populations show a correlation between infection status or use of antiviral therapies, while some do not. Some researchers have proposed that significant contributions to neurodegenerative disease require the interacting presence of several viral infections, which if true would explain why studies assessing infection status for a single virus produce mixed results.
If looking at only biological mechanisms, such as HSV-1 driving greater accumulation of amyloid-β in the aging brain, or the disruptions to immune function generated by cytomegalovirus, it all sounds quite compelling. But at the end of the day, researchers have be to able to demonstrate a robust association in epidemiological data for the viral contribution to Alzheimer’s disease and other neurodegenerative conditions to be taken seriously. At the moment researchers are still in search of that robust correlation, and as a consequence this remains an exploratory part of the field.
HSV-1 as a Potential Driver of Alzheimer’s Disease
Globally, approximately 4 billion people, or 64% of the population under the age of 50, are infected with herpes simplex virus type 1 (HSV-1). Antiviral medications such as acyclovir, famciclovir, and valacyclovir are prescribed to symptomatic patients. A complete cure for HSV-1 remains elusive in 2025, as these medicines do not eliminate the virus. After an initial infection, HSV-1 often enters a latent state, which can be reactivated, causing recurrent outbreaks, symptomatic or asymptomatic. Emerging evidence suggests that HSV-1 may contribute to neurodegeneration, particularly in Alzheimer’s disease (AD), potentially through mechanisms such as chronic neuroinflammation, amyloid-beta (Aβ) and hyperphosphorylated Tau accumulation, oxidative stress, and synaptic dysfunction. Moreover, HSV-1 proteins have been detected in the hippocampus and thalamus, both of which are affected in AD. However, the role of HSV-1 in dementia remains unclear.
In this review, we examine current evidence on the potential role of HSV-1 in the pathogenesis of dementia and consider whether targeting HSV-1 could be a viable strategy for preventing progressive neurodegeneration. Although many studies have demonstrated an association between HSV-1 and AD, further exploration is needed to determine whether HSV-1 infection is a cause or a consequence of AD degeneration. Because HSV-1 is latent in the trigeminal ganglion and travels to the brain during reactivation, an animal model that can physiologically mimic human-brain conditions remains a challenge. Thus, future studies should examine possible experimental models in order to determine the causality between HSV-1 and AD.
AD is characterized by progressive memory impairment, executive dysfunction, and visuospatial impairment. Several studies have shown that neurotropic viral infections serve as a risk factor for AD onset and progression. Regarding the contribution of HSV-1 infection to AD onset, the studies started with the observation demonstrating the association between HSV-1 DNA and amyloid plaques. 72% of HSV-1 DNA was associated with plaques, whereas only 24% of HSV-1 DNA was associated with plaques in normal brains. Furthermore, HSV-1 DNA and proteins were found in the central nervous system, particularly in the hippocampus and thalamus, which are predominantly affected in AD, supporting the association between HSV-1 infection and AD.
In an epidemiological study, a meta-analysis revealed a positive correlation between anti-HSV-1 acyclovir treatment and the potential reduction in the risk of AD development or slowing down the progression of AD symptoms. However, the analysis may be limited by the lack of data from prospective randomized controlled clinical trials. A Phase II randomized, double-blind, placebo-controlled trial of valacyclovir in patients with mild AD and evidence of HSV-1/2 infection was recently completed (NCT03282916). After 78 weeks of treatment, valacyclovir did not slow disease progression. However, it remains unclear whether a longer treatment duration or intervention at an earlier disease stage might be required to observe therapeutic effects.
Overall, the mechanisms underlying HSV-1 in regulating AD progression are unclear, and further experimental studies are needed to confirm the epidemiological association between HSV-1 and AD. In addition, it remains unclear whether the increased presence of HSV-1 DNA and proteins in brain regions is a consequence of AD-associated immune dysfunction, making the brain more susceptible to infection.
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