Platelet proteomic signatures of amyloid β-positive mild cognitive impairment and Alzheimer’s disease

Early detection of Alzheimer's disease (AD) is critical for preventing disease progression. Blood platelets have emerged as a useful peripheral source for AD diagnosis. However, the identification of proteomics-based platelet biomarkers of mild cognitive impairment (MCI) and AD in relation to amyloid β (Aβ) deposition remains largely unexplored. In this study, we compared four groups from 18 participants: subjective memory impairment (SMI, n = 4) as cognitive normal controls, MCI without Aβ deposition (MCI-A(+), n = 5), MCI with Aβ deposition (MCI-A(-), n = 5), and AD (n = 4). We conducted in-depth platelet protein profiling using high-throughput LC-MS/MS with tandem mass tag labeling. Among the total 4,524 proteins detected, we identified both unique and overlapping differentially expressed proteins in MCI-A(+), MCI-A(-), and AD compared with SMI. Hierarchical clustering analysis revealed seven distinct patterns of proteomic alterations across groups. Functional network and gene ontology enrichment analyses indicated that each cluster was associated with specific processes, including platelet activation, AD, and apoptotic signaling pathways. Notably, upregulated proteins in MCI-A(-) and AD were linked to endomembrane system organization. Furthermore, we quantified the relative abundance of multiple protein candidates that were significantly altered in MCI-A(-) and AD compared with SMI and MCI-A(+). Our findings highlight several platelet proteins-ATP6V0C, AP4B1, RAB2B, PSMD9, FKBP1B, and mTOR-as potential molecular targets for predicting AD at the stage of MCI with Aβ deposition, providing new insights into amyloid-related neurodegeneration.