Scientists have uncovered a link between human herpesvirus and Alzheimer's, showing how viral-driven transposable elements accelerate brain degeneration. The good news? Antiviral drugs like valacyclovir may help slow or even prevent the disease.
Study: Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer's disease. Image Credit: Design_Cells / Shutterstock.com
A recent study published in Alzheimer’s & Dementia examines how human herpesvirus (HHV) infection contributes to the pathophysiology of Alzheimer’s disease (AD).
How does herpes infection impact AD risk?
Over 30 years ago, researchers discovered a greater prevalence of human simplex virus type 1 (HSV-1) DNA in the brains of individuals who died from AD as compared to healthy individuals. In this population, the incidence of AD more frequently occurred in those with a history of HSV-1 infection rates, with apolipoprotein 4 (APOE4) carriers with recurrent HSV-1 reactivation rates also at a greater risk of developing AD.
Previous in vitro and in vivo rodent studies have reported that mice infected with HSV-1 develop both neuroinflammation and protein abnormalities, including amyloid-beta and tau changes characteristic of AD. In the current study, the researchers investigated the potential role of HHV-infection-associated transposable elements (TEs) in AD-specific neurodegeneration.
What are transposable elements?
TEs are mobile genetic elements (MGEs) or small pieces of genetic material that can become activated and subsequently move throughout the genome. As TEs merge together with DNA at their new location, they can cause significant interruptions to nearby genes, thereby changing the way these genes function.
Aging is associated with increasing TE activation. Previously, changes in TE activation have been implicated in several cognitive disorders.
About the study
Data on gene function was obtained from the functional genomics databases of the Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks. Single-cell transcripts were examined from the forebrain of deceased individuals with and without advanced AD to identify molecular-level alterations in the HHV-positive AD brain signaling vulnerability to neurofibrillary tangle (NFT) formation.
TE activation changes were assessed by cell subset. The association of activated TEs with amyloid beta (Aβ) and tau pathology was also examined. HHV-positive forebrain were examined to validate the observations.
Study findings
HHV ribonucleic acid (RNA) was more frequently identified in the brains of individuals with the APOE4 genotype. Increased expression of HHV RNA was also observed in the brains of individuals with more advanced AD as assessed by the Braak staging and Consortium to Establish a Register for Alzheimer’s Disease (CERAD) scores.
Several TEs were extensively activated in the HHV-positive AD brains but not those of healthy individuals. Furthermore, TE changes in AD-affected brains reflected the presence of neuroinflammation and microglial activation.
The long interspersed nuclear element (LINE) class was the most commonly upregulated TE, specifically the LINE1 subfamily TEs. These TEs were activated in astrocytes and microglia within AD brains, which suggests their role in stimulating cell survival and proliferation through a G protein-coupled receptor (GPCR).
LINE1 TEs also upregulated the target genes lncRNA nuclear enriched abundant transcript 1 (NEAT1) and inositol-triphosphate 3-kinase B (ITPKB). NEAT1 has been implicated in AD progression and neuroinflammation.
Taken together, these findings indicate that HHV infection may cause neuroinflammation through the activation of LINE1 in astrocytes.
The expression of the ten most differentially increased TEs in AD brains was significantly different than that observed in healthy individuals, which indicates the diagnostic potential of these TEs. Female-specific changes were also observed in some LINE1 subfamily TEs.
TE dysregulation is potentially correctable by antivirals
Anti-HHV drugs, specifically valacyclovir and acyclovir, partially corrected widespread TE activation in response to HHV in HSV-1-infected brain organoids.
This in vitro observation was validated setting by examining data from 80 million health records on a public database using artificial intelligence to determine AD incidence following antiviral prescription for HSV-1 infection. This analysis identified a significantly lower incidence of AD in individuals prescribed valacyclovir and acyclovir, with these improvements more prominent among women than men, as well as individuals 75 years of age and older.
What is valacyclovir?
In vitro assays indicated that valacyclovir treatment did not prevent the formation of tau clumps. However, valacyclovir treatment accelerated their breakdown, thereby preventing their progression to NFTs.
Valacyclovir treatment also reduced tau phosphorylation and inactivated LINE TEs, in addition to reversing the aggregation of LINE1-open reading frame 1p (ORF1p) by stimulating autophagy without affecting protein expression levels.
Anti-HHV drugs may suppress virus replication during reactivation events. By preventing viral proliferation within infected host cells, these drugs may reduce the future risk of AD.
Conclusions
TE-based therapies may offer potential therapeutic approaches for the prevention and treatment of HHV-associated AD or other AD-related dementias if broadly applied.”
Journal reference:
- Feng, Y., Cao, S., Shi, Y., et al. (2025). Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer's disease. Alzheimer’s & Dementia. doi:10.1002/alz.14595.