Proteomic analysis of human chronic traumatic encephalopathy brain implicates proteasome and ribosome dysfunction in disease severity.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that occurs in individuals with repeated head impacts (RHI) exposure, including contact sport athletes, military personnel, and domestic abuse victims. Despite growing recognition of CTE, the molecular mechanisms underlying the disease process remain poorly understood. This study aims to identify proteomic alterations associated with CTE pathology and clinical features to elucidate key biological pathways involved in disease pathogenesis. Methods: SomaScan 7 k high-throughput proteomics was performed on 204 dorsolateral prefrontal cortex samples from the Boston University CTE Center Brain Bank. We identified differentially expressed proteins associated with CTE, hyperphosphorylated tau (ptau) pathology, duration of contact sports play, dementia status, and Cognitive Difficulty Scale (CDS) scores. Results: Gene set enrichment analysis revealed that proteasome subunit proteins and related pathways were strongly associated with CTE severity and correlated with years of contact sports play. Reduction in ribosomal proteins and pathways was closely associated with ptau burden. Additionally, multiple models demonstrated significant alterations in MAPK-related cell signaling pathways. Conclusions: These findings advance our understanding of the postmortem brain CTE molecular profile and identify biological and molecular processes correlated with key pathological features of the disease. Validation of these results could inform the development of diagnostics and treatments for CTE. Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-026-00045-w.