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Journal article
The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review
Brain, behavior, and immunity, Vol.132, 106201
2026
Abstract
Background
Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.
Methods
We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.
Results
Twenty-six studies (N ranges: 6–485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95 % CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.
Conclusions
The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs’ role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.
Details
- Title
- The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review
- Authors/Creators
- Leta Adugna GeletaCaitlin DoyleFleur C GartonMegan FowlerJillian M Carr - Flinders UniversityAnthony Akkari - Murdoch University, Personalised Medicine CentreAllan McRae - The University of QueenslandMary-Louise Rogers - Flinders UniversityIqbal MadakkatelBeben Benyamin
- Publication Details
- Brain, behavior, and immunity, Vol.132, 106201
- Publisher
- Elsevier Inc.; SAN DIEGO
- Number of pages
- 13
- Identifiers
- 991005834966507891
- Copyright
- © 2025 The Author(s).
- Murdoch Affiliation
- Personalised Medicine Centre; Centre for Molecular Medicine and Innovative Therapeutics
- Resource Type
- Journal article
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