Background: Chronic hydrocephalus (CH) is a heterogeneous neurological disorder characterized by persistent ventricular enlargement and neurovascular dysfunction in the aging brain. Despite its clinical relevance, genetically anchored RNA biomarkers reflecting CH-associated metabolic and stress-related pathology remain poorly defined. Methods: We performed bulk RNA sequencing of postmortem caudate nucleus tissue from individuals with CH and age-matched neurologically normal controls. Disease-associated transcriptional programs were identified using principal component analysis (PCA), unsupervised hierarchical clustering, and gene set enrichment analysis (GSEA). Key candidate transcripts were validated by RT-PCR. Comparative genomic analyses across mouse, rat, pig, and human genomes examined transcript length, chromosomal positioning, and nucleotide composition. Results: PCA of the top 1,000 most variable transcripts demonstrated robust separation between CH and controls. Analysis of transcripts ranked 1,001-2,000 independently reproduced disease segregation, indicating distinct transcriptional programs. GSEA revealed significant enrichment of xenobiotic metabolism and oxidative stress pathways, with pyruvate dehydrogenase kinase 4 ( Conclusion: PDK4: is identified as a prominent RNA marker of chronic hydrocephalus in the elderly, providing a neurogenomic foundation for future fluid-based RNA biomarker development.