Discovery of plasma biomarkers related to blood-brain barrier dysregulation in Alzheimer's disease

Abstract

Introduction: Blood-based biomarkers are quantitative, non-invasive diagnostic tools. This study aimed to identify candidate biomarkers for Alzheimer’s disease (AD) using publicly available omics datasets, using the hypothesis that with blood-brain barrier dysfunction in AD, brain-synthesized proteins can leak into plasma for detection. Methods: Differential abundance results of plasma and brain proteomic datasets were integrated to obtain a list of potential biomarkers. Biological validity was investigated with intercellular communication and gene regulatory analyses on brain single-cell transcriptomics data. Results: Five proteins (APOD, B2M, CFH, CLU, and C3) fit biomarker criteria. 4 corresponding transcripts (APOD, B2M, CLU, and C3) were overexpressed in AD astrocytes, mediated by AD-related dysregulations in transcription factors regulating neuroinflammation. Additionally, CLU specifically induced downstream expression of neuronal death genes. Discussion: In conclusion, a 5-protein panel is shown to effectively identify AD patients, with evidence of disease specificity and biological validity. Future research should investigate the mechanism of protein leakage through the blood-brain barrier.