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The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review
Journal article   Open access   Peer reviewed

The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review

Leta Adugna Geleta, Caitlin Doyle, Fleur C Garton, Megan Fowler, Jillian M Carr, Anthony Akkari, Allan McRae, Mary-Louise Rogers, Iqbal Madakkatel and Beben Benyamin
Brain, behavior, and immunity, Vol.132, 106201
2026
DOI: https://doi.org/10.1016/j.bbi.2025.106201
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Published2.88 MBDownloadView
CC BY V4.0,  Open Access

Abstract

Human endogenous retroviruses Neurodegenerative diseases Systematic review
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.

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Collaboration types
Domestic collaboration
International collaboration
Citation topics
1 Clinical & Life Sciences
1.54 Molecular & Cell Biology - Genetics
1.54.1122 Transposable Elements
Web Of Science research areas
Immunology
Neurosciences
Psychiatry
ESI research areas
Neuroscience & Behavior
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