Transposable elements in aging brains were linked to herpesvirus RNA.
A team lead by Cleveland Clinic’s Genome Center, Feixiong Cheng, PhD, reported evidence that associating molecular, clinical and neuropathological features of Alzheimer’s with human herpesvirus infection. Dr. Cheng’s hypothesis was that latent herpesvirus infections could trigger AD by directly activating the transposable elements which his laboratory and previously connected to disease progression in aging brains. The same group reported last year that there is widespread transposable element (TE) dysregulation in human aging brains with AD (Feng 2024).
The group found that TE dysregulation correlated with HHV-6 positive human Alzheimer’s brains, including astrocyte specific upregulation of the LINE1 (long interspersed nuclear element 1) subfamily TEs. The LINE1 dysregulation could be partially reversed using HHV antivirals valacyclovir and acyclovir in their HSV-1 infected human brain organoid model.
The group analyzed bulk RNA-seq data in two large human brain biobanks: the Religious Orders Study and Rush Memory and aging project (ROS/MAP) and the Mount Sinai Brain Bank (MSGG) as well as single-cell RNA sequencing data from HHV6 infected forebrain organoids to investigate HHV-infection associated TE dysregulation.
Between the two biobanks they studied 393 AD cases and 194 cognitively healthy controls and noted widespread TE activation in the HHV positive AD brains, and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score and CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) score.
The sequential process outlined by the authors is that the process begins as herpesviruses becomes more active as our immune systems falter as natural consequence of aging. The herpesviruses then activate transposable elements such as those in the LINE1 subfamily, which in turn disrupts key genetic processes in the brain resulting in the accumulation of tau and associated inflammation and neurodegeneration.
Although the authors chose HSV-1 for their organoid model, the predominant HHV-6 RNAs found in brain cells were HHV-6A, HHV-6B and HHV-7.
Proposed transposable element upregulation-associated AD-like mechanisms in human AD brains.
As shown with other studies, the investigators utilized real-world data from the Optum database (604,026 records) to demonstrate that treatment with valacyclovir (HR =.803) and acyclovir (HR= 0.87) significantly reduced the incidence of AD, particularly in women and older adults.
Read the full paper: Feng 2025