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Alzheimer's disease, whose prevalence increases with demographic aging, is raising growing concerns about a possible link to the herpes simplex virus type 1 (HSV-1). Ongoing research is examining the potential role of this virus in the development and progression of the disease, although no definitive conclusions have been reached yet.
Alzheimer's disease (AD) represents a major public health challenge in a world where demographic aging is advancing rapidly. According to updated data from the World Health Organization (WHO) as of October 1, 2024, the percentage of the global population aged over 60 is expected to nearly double between 2015 and 2050, from 12% to 22%, representing almost 2.1 billion people. Such a demographic shift is likely to intensify the impact of AD, which remains incurable to this day. Indeed, 2024 US national statistics show that about 5% of individuals aged 65 to 74, 13.2% of those aged 75 to 84, and 33.4% of those over 85 were affected by this condition, with prevalence steadily increasing. Its etiology remains unknown, although a recent hypothesis suggests a potential role of HSV-1, the virus responsible for cold sores, in the development of the disease.
An Old but Persistent Hypothesis
For several decades, biomedical research has intensely focused on the relationship between viral infections and human diseases. In 2024, Roberto Mallone's team from the Cochin Institute reported a possible association between the Coxsackie B virus and type 1 diabetes in Science Advances. In 2022, Alberto Ascherio's team at Harvard University established a link between the Epstein-Barr virus and multiple sclerosis, with their findings published in Science. In 1976, Harald zur Hausen demonstrated that certain human papillomavirus (HPV) types play a role in the development of cervical cancer, a discovery that earned him the Nobel Prize in Physiology or Medicine in 2008.
Recently, scientific studies have suggested that various viruses could contribute to the onset and/or progression of AD. However, the extent of their involvement and the mechanisms through which they might increase this risk remain poorly understood. The hypothesis linking HSV-1 to AD is supported by several findings, including those from the French Trois Cités (3C) cohort. This study, involving nearly 10,000 participants aged 65 and older from three French cities (Bordeaux, Dijon and Montpellier), was conducted over a ten-year period. Through specific assays, researchers identified those infected with HSV-1. At the end of the follow-up period, 19.7% of participants had developed dementia. However, no correlation was found between the virus and AD, except for patients with a specific genetic risk factor (APOE ε4), in whom the infection was associated with a 3 to 4 times higher risk compared to uninfected individuals.
High-Resolution Imaging
A new study published on January 2 in Cell Reports also highlights a potential link between HSV-1 and the development of AD, exploring this hypothesis in much greater depth. Primarily associated with vesicular lesions on the lips, this neurotropic virus (which has an affinity for the nervous system) is well documented for its ability to infect neurons, where it can persist in a dormant (inactive) state for years or reactivate intermittently. Could this reactivation disrupt neuronal processes and promote the development and progression of AD? This is precisely the question the study's authors aim to answer. One of the main challenges in demonstrating such a link lies in the difficulty of detecting the virus in the brains of patients.
Although HSV-1 can be detected in serum and cerebrospinal fluid (the clear fluid that surrounds and protects the brain and spinal cord), it is rarely found in brain samples. Researchers have hypothesized that HSV-1 may be present in the brains of AD patients as proteins, but at levels undetectable by conventional methods. To explore this, they used an innovative technique to amplify samples, enabling high-resolution imaging and spatial mapping of HSV-1 proteins. The observations revealed that these proteins were particularly abundant in brain regions associated with AD. This suggests that the virus could interact directly with the disease's pathological mechanisms. But how?
Defense Mechanism
One of the most interesting findings of this study is the discovery that the tau protein, whose abnormal phosphorylation is a key marker of AD, could paradoxically play a protective role against viral infections. The researchers observed that hyperphosphorylated tau appears to inhibit the production of viral proteins in infected neurons, reducing cell death from 64% to 7%. However, when this phosphorylation becomes chronic, it can induce toxicity, contributing to the known neuronal dysfunctions and exacerbating the pathological effects of AD, particularly in response to factors like HSV-1. Nonetheless, no interaction was detected between this virus and amyloid plaques, another hallmark of AD, leading researchers to speculate that amyloid proteins might be involved in the immune response to bacterial or fungal infections.
The authors of this publication highlight that what has been perceived for decades as the pathological signature of AD (hyperphosphorylated tau and amyloid plaques) could actually be a cellular defense mechanism. Such a hypothesis could partly explain the limited effectiveness of anti-amyloid treatments, which has sparked a widespread debate about their utility and safety. This controversy intensified following the rejection of lecanemab (an anti-amyloid therapeutic antibody) by the European Medicines Agency (EMA) in July 2024, even though it had been approved by the US Food and Drug Administration (FDA) a year earlier. This rejection echoes the experience of the first anti-amyloid treatment, aducanumab, which was also denied market approval in Europe in 2022 after being approved by the FDA.
A Potential Therapeutic Pathway
If HSV-1's involvement in AD is proven, it could open new therapeutic avenues for treating the disease. Studies are currently ongoing to determine whether antiviral drugs could offer a treatment option for these patients, slowing or halting disease progression. A large study conducted by Tzeng et al. in Taiwan, including 33,448 patients, found that people infected with HSV-1 were 2.56 times more likely to develop dementia. However, a reduction in this risk was observed in infected patients treated with antivirals. While a vaccine for HSV-1 is under development, vaccination against the varicella-zoster virus (VZV) has shown a reduction in the incidence of neurological diseases and dementia. That said, until the results of future studies are available, this hypothesis remains to be closely monitored, in the hope of finding new solutions for the more than 55 million people affected by AD worldwide.
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