Identification of high‐performance blood‐based biomarkers for early screening and staging of Alzheimer’s disease by large‐scale plasma proteomic profiling in mild cognitive impairments

Abstract Background Early detection of Alzheimer's disease (AD), particularly during the mild cognitive impairment (MCI) stage, is crucial for effective intervention and treatment. However, existing diagnostic methods, through cognitive assessments, brain imaging, or cerebrospinal fluid profiling, are subjective, expensive or invasive. We previously showed that the plasma proteome is altered in AD, suggesting the feasibility of utilizing blood biomarkers for AD detection. Therefore, to develop a blood test for early screening and staging of AD, it is important to identify blood biomarkers associated with MCI/early AD and the features of AD progression. Method We conducted a comprehensive profiling of the plasma proteome of MCI by measuring 1,160 proteins in a Hong Kong Chinese cohort, to identify novel blood biomarkers for MCI/early AD. We further developed a biomarker panel based on the identified MCI/AD‐associated blood biomarkers and validated its performance in an independent amyloid‐PET‐defined cohort. Result We identified 496 proteins that were dysregulated in MCI plasma, and these proteins, involved in different biological processes, exhibited distinct dysregulating patterns with disease progression. We further categorized these proteins into different groups based on their dysregulating patterns. By performing co‐expression network analysis, we identified an 18‐protein panel that captures the profile changes of plasma proteome in MCI and AD. This panel accurately classified MCI (AUC = 0.913‐0.925) and AD (AUC = 0.970‐0.993) in two independent cohorts. Moreover, this panel correlates with cognitive decline and the development of Aβ pathology in the brain, which outperforms some of the existing plasma ATN biomarkers. Conclusion This study comprehensively profiled the MCI plasma proteome and demonstrates the feasibility of a blood‐based biomarker assay for early detection and staging of MCI and AD, potentially facilitating early screening, monitoring, and intervention in future clinical settings.