Astrocytoma-Specific Prognostic Associations of Amyloid-Related Biological Processes

Background: Amyloid-related pathways are well studied in neurodegenerative diseases but remain poorly characterized in gliomas. Amyloid-related transcriptional programs in low-grade gliomas (astrocytoma grade II-III) and oligodendrogliomas, and their association with patient survival, were analyzed in this study. Methods: Transcriptomic data from 193 grade II-III astrocytomas and 191 oligodendrogliomas were analyzed to evaluate histology-specific expression patterns and prognostic significance. Differential and single-sample gene set enrichment analyses (ssGSEA) were used to calculate per-sample enrichment scores for 30 amyloid-related Gene Ontology biological process gene sets across the combined cohort. These scores were used to compare pathway activity between grade II-III astrocytoma and oligodendroglioma samples. Pathway-level survival analyses were performed for each tumor type using ssGSEA enrichment scores to evaluate associations with overall survival. Results: Distinct amyloid-related transcriptional programs were identified between glioma subtypes. Grade II-III astrocytomas showed enrichment of pathways related to amyloid precursor protein (APP) processing and amyloid-β clearance, whereas oligodendrogliomas were enriched in lipid transport and negative regulation of amyloid formation. Survival analyses revealed that higher activity of the positive regulation of APP biosynthetic process and amyloid-β clearance by transcytosis was significantly associated with worse overall survival in grade II-III astrocytoma, but not in oligodendroglioma. Gene-level analyses in astrocytoma demonstrated consistent survival associations across multiple genes within these pathways, supporting coordinated pathway-level effects rather than isolated single-gene prognostic markers. Conclusions: Amyloid-related transcriptional programs differ substantially between diffuse glioma subtypes. Increased APP biosynthesis and amyloid-β transcytosis pathways are associated with poorer survival specifically in grade II-III astrocytoma, suggesting a potential role for amyloid metabolism in tumor progression. These findings identify APP-related pathways as candidates for further mechanistic investigation and potential therapeutic targeting in grade II-III astrocytoma.