February 27, 2025 — A groundbreaking study published in Alzheimer’s & Dementia sheds new light on the link between human herpesvirus (HHV) infection and Alzheimer’s disease (AD). The research reveals how HHV infections, particularly those caused by herpes simplex virus type 1 (HSV-1), may contribute to the pathophysiology of Alzheimer’s, highlighting a potential new avenue for treatment.
The Role of Herpes Infection in Alzheimer’s Risk
The connection between HSV-1 and Alzheimer’s disease has been a topic of research for over 30 years. Early studies found that HSV-1 DNA was more prevalent in the brains of individuals who died from Alzheimer’s, compared to healthy individuals. This virus was more commonly found in those with a history of HSV-1 reactivation, especially among apolipoprotein E4 (APOE4) carriers—a genetic group at heightened risk for developing Alzheimer’s.
Previous rodent studies have also shown that HSV-1 infection can lead to neuroinflammation and protein abnormalities, such as amyloid-beta and tau deposits, which are hallmark features of Alzheimer’s disease. The new study dives deeper into the mechanisms by which HSV-1 infection contributes to AD-specific neurodegeneration, focusing on transposable elements (TEs), which are genetic materials linked to the development of Alzheimer’s.
What Are Transposable Elements?
Transposable elements (TEs) are small, mobile pieces of genetic material that can move throughout the genome. When TEs insert themselves into new genomic locations, they can disrupt nearby genes, affecting gene function. Aging is associated with increasing activation of TEs, and changes in TE activation have been implicated in several cognitive disorders, including Alzheimer’s disease.
Study Methodology and Findings
Data for this study was obtained from brain biobanks such as the Religious Orders Study, the Rush Memory and Aging Project (ROS/MAP), and Mount Sinai Brain Bank (MSBB). Researchers analyzed gene expression and single-cell transcripts from the forebrains of deceased individuals, both with and without advanced Alzheimer’s, to identify molecular alterations caused by HHV infection.
The study discovered that HHV ribonucleic acid (RNA) was more prevalent in the brains of individuals carrying the APOE4 genotype. Furthermore, increased expression of HHV RNA was observed in individuals with more advanced stages of Alzheimer’s disease, as measured by Braak staging and CERAD scores. The most significant finding was the extensive activation of TEs in the brains of individuals with HHV-associated Alzheimer’s, a phenomenon not seen in healthy brains.
The long interspersed nuclear element (LINE) class, particularly the LINE1 subfamily, was the most frequently upregulated TE in HHV-positive AD brains. These TEs were activated in astrocytes and microglia, cells crucial to the brain’s immune response, suggesting that LINE1 activation plays a role in neuroinflammation and the development of Alzheimer’s pathology.
TE Activation and Neuroinflammation
The activation of LINE1 TEs triggered several downstream effects, including the upregulation of genes associated with cell survival and proliferation. Notably, these include the genes NEAT1 and ITPKB, both of which are linked to neuroinflammation and Alzheimer’s progression.
This finding implies that HHV infection could contribute to neuroinflammation by activating LINE1 TEs in astrocytes, which could play a pivotal role in Alzheimer’s disease progression. Additionally, the research highlighted sex-specific differences, noting that certain LINE1 subfamily TEs were more actively expressed in women with Alzheimer’s.
Potential for Antiviral Treatment
The study also explored the potential of antiviral drugs in mitigating the effects of HHV infection on Alzheimer’s development. In vitro experiments with brain organoids infected by HSV-1 revealed that antiviral drugs such as valacyclovir and acyclovir could partially reverse the widespread activation of TEs induced by HHV infection.
Further analysis using data from 80 million health records found that individuals prescribed valacyclovir and acyclovir had a significantly lower incidence of Alzheimer’s, with particularly notable effects among women and those aged 75 and older. While valacyclovir did not prevent tau aggregation, it accelerated the breakdown of tau clumps, reducing their progression into neurofibrillary tangles (NFTs)—a key feature of Alzheimer’s pathology.
Valacyclovir treatment also reduced tau phosphorylation, inactivated LINE TEs, and promoted autophagy (the process by which cells break down and remove waste material). These effects may help reduce the accumulation of Alzheimer’s-related proteins, ultimately lowering the risk of developing the disease.
Conclusion and Future Implications
The findings of this study suggest that HHV infection, particularly through the activation of TEs like LINE1, plays a significant role in the neuroinflammation and protein abnormalities characteristic of Alzheimer’s disease. This research opens new possibilities for Alzheimer’s prevention and treatment through antiviral therapy, with drugs like valacyclovir showing promise in reducing disease risk, particularly for older adults and women.
As the link between HHV infection and Alzheimer’s becomes clearer, antiviral drugs may soon be considered as part of the therapeutic arsenal for reducing the risk and progression of Alzheimer’s disease, providing a potential avenue for both prevention and treatment.
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