Blood-Based Proteomic Profiling to Identify Biomarkers Candidates and Shed Light on the Pathogenic Pathways Underlying Cognitive Dysfunction

Dementia is a progressive and debilitating neurological disease that affects millions worldwide. Early diagnosis and effective treatments are crucial in managing the disease. This study sought to pinpoint minimally invasive biomarkers associated with dementia by analysing plasma proteome and autoantibody profiles in individuals with dementia and mild cognitive impairment (MCI). Utilising cutting-edge technologies, we measured over 1200 proteins and investigated more than 1600 autoantibodies in a cohort of 122 participants. Our exhaustive screening revealed dysregulation of several proteins in the plasma of dementia and MCI patients and established two panels of 17 and 8 biomarkers that successfully differentiated individuals with dementia from cognitively normal controls and MCI with an area under the curve (AUC) of 0.98 ± 0.02, and 0.87 ± 0.07, respectively. Six proteins have consistently emerged in both diagnostic models, including NEFL, WNT9A, IL17D, IGFBP2, KLK4, and PGF. The identified proteins, linked to dementia, were connected to immune response, vascular injury, and the organisation of the extracellular matrix pathways.

Furthermore, a targeted examination of proteins tied to dementia revealed elevated plasma levels of NEFL, GFAP and UCHL1 in dementia cases, indicating neurodegeneration, neuroinflammation and involvement in protein degradation pathways, respectively. These biomarkers were associated with poor cognitive performance and showed the highest discriminatory ability in identifying dementia cases with AUCs of 0.93, 0.89 and 0.77, respectively. Moreover, we found significantly altered autoantibody responses in dementia and MCI plasma, including five common autoantibodies (anti-CAMK2A, CKS1B, ETS2, MAP4, and NUDT2). Notably, several proteins targeted by dysregulated autoantibodies in dementia were enriched in neuro-related pathways such as the neurotrophin signalling pathway and apoptosis. In conclusion, our proteomics and autoantibody profiling identified potential blood-based signature markers of dementia and MCI subjects.

Further research is required to validate these biomarkers and investigate the potential underlying mechanisms contributing to the development of dementia. Early detection of these biomarkers could enhance early diagnosis, aid in developing targeted therapies, and provide valuable insights into dementia's pathogenesis.