Virtual reality technology for the treatment of mild cognitive impairment: Changes in immune-related genes and alternative splicing and implications for treatment efficacy

Abstract

Background: Mild Cognitive Impairment (MCI) is recognized as a critical transitional stage from the preclinical phase of Alzheimer’s Disease (AD) to overt dementia, while AD is a progressive neurodegenerative disorder with limited therapeutic options. Virtual Reality (VR) therapy has emerged as a promising non-pharmacological intervention for cognitive disorders. The purpose of this study was to investigate the molecular mechanisms underlying VR therapy in AD-MCI.

Methods: RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from healthy volunteers (C, n=5), AD-MCI patients before VR intervention (ADB, n=5), and after completion of the VR- based Cognitive Rehabilitation Software (VR-CRS) program (ADA, n=3). We conducted differential expression analysis, functional enrichment and trend clustering of genes. Alternative splicing events were also analyzed and co-expression networks were constructed with RNA-binding proteins.

Results: Principal component analysis revealed a distinct shift in the global gene expression profile following VR-CRS intervention. Differential expression analysis identified 421 upregulated and 186 downregulated genes in ADB vs. C, and 165 upregulated and 1002 downregulated genes in ADA vs. ADB. A core set of 251 genes was consistently altered by AD-MCI and modulated by VR-CRS. Functional enrichment highlighted the significant involvement of immune and inflammatory response pathways. Trend clustering pinpointed a key gene cluster (including transcription factors ZFP36, FOS, JUN, FOSB and the mitochondrial gene PMAIP1) that was upregulated in ADB and decreased to normal after VR-CRS. These genes showed significant correlations with immune cell proportions. Furthermore, widespread differential alternative splicing events were observed, affecting genes involved in cell cycle, immune response and neural function (e.g. AMPD2, MALAT1, DDX3X), which were also partially restored by VR-CRS treatment.

Conclusions: VR-CRS intervention is associated with transcriptomic changes in patients with AD-MCI, primarily involving modulation of immune and inflammatory pathways. It also appears to influence alternative splicing patterns. These preliminary findings provide novel molecular insights into the potential mechanisms of VR-CRS, suggesting it may act as a multi-faceted intervention targeting both transcriptional and post-transcriptional networks.