Early detection of Alzheimer’s disease (AD) can provide an effective scheme to prevent the disease progression. Studies have shown that blood platelets are a useful peripheral source for AD diagnosis. Identifying proteomics-based platelet biomarkers of mild cognitive impairment (MCI) and AD related to amyloid  peptide (A) deposition, which remains largely unexplored, is valuable. This study compared four groups from 18 human participants. subjective memory impairment (SMI, n = 4) as cognitive normal control, MCI without A deposition (MCI-A(), n = 5), MCI with A deposition (MCI-A(), n = 5), and AD (n = 4). We performed in-depth platelet protein profiling using high-throughput LC–MS/MS with tandem mass tag (TMT) labeling.MCI-A(), MCI-A(), and AD in comparison to SMI. Hierarchical clustering analysis revealed seven different patterns of proteomic alterations among functional network and gene ontology (GO) enrichment showed a distinct feature of each cluster specific processes such as platelet activation, AD, and apoptotic signaling pathways. In particular, our data indicated that upregulated proteins in MCI-A() and AD are associated with endomembrane system organization. Moreover, we determined the relative abundance of multiple protein candidates that significantly changed in MCI-A() and AD compared to SMI and MCI-A(). Our data demonstrated that several platelet proteins, including ATP6V0C, AP4B1, RAB2B, PSMD9, FKBP1B, and mTOR, can be key molecular targets for predicting AD at the stage of MCI with A deposition and provide insights into amyloid-related neurodegeneration.