Serum proteomics associated with PTSD and MCI: An exploratory Olink® Neurology panel study

Introduction Posttraumatic stress disorder (PTSD) may develop following exposure to traumatic events and is particularly important in South Africa due to the high prevalence of widespread trauma and interpersonal violence. Increasing evidence connects PTSD with mild cognitive impairment (MCI). Investigating the proteomic signatures of this comorbidity offers a unique opportunity to examine the relationship between PTSD and MCI to better understand the molecular pathways contributing to cognitive vulnerability in a South African cohort. Methods The study included 88 participants grouped by PTSD with/without MCI and trauma-exposed controls (TEC) with/without MCI ( n = 22 each), recruited as part of the South African SHARED ROOTS study. PTSD was diagnosed using CAPS-5, and MCI was assessed using the Montreal Cognitive Assessment. Serum protein expression was profiled using the Olink® Neurology panel. Differential protein expression and pathway enrichment analyses were conducted for a) PTSD vs. TEC, b) PTSD+MCI vs. TEC+MCI, c) TEC+MCI vs. TEC-MCI, and d) PTSD+MCI vs PTSD-MCI, correcting for age and sex. Results We identified nine proteins associated with PTSD only, and five proteins associated with MCI-related comparisons. WFIKKN1 (WAP, Follistatin/kazal, Immunoglobulin, Kunitz and Netrin domain-containing protein) was identified in the PTSD+MCI vs PTSD-MCI group. GSEA analyses revealed pathways related to morphogenesis, signalling, and nervous system development in the three MCI-related comparisons. The NABA matrisome pathway was consistently enriched in trauma-exposed groups with MCI, regardless of PTSD status. Conclusion WFIKKN1 emerged as a shared marker in PTSD and TEC groups with MCI, suggesting a possible role for the extracellular matrix (ECM) in cognitive impairment. The enrichment of proteins comprising the NABA matrisome pathway in MCI supports the possibility of ECM remodelling in cognitive impairment, as the matrisome comprises genes involved in ECM structure. Alterations in ECM components could implicate neurodegeneration and synaptic plasticity relevant to both PTSD and MCI. These findings underscore the importance of cognitive function in PTSD and may guide future biomarker and intervention strategies.