Nanoparticle-enriched mass spectrometry enables comprehensive plasma proteomics and reveals novel candidates for mild cognitive impairment

Mild cognitive impairment (MCI) is a precursor to Alzheimer’s disease (AD), underscoring the need for reliable biomarkers for early identification. Here, we employed an automated nanoparticle-enrichment sample preparation platform combined with liquid chromatography–tandem mass spectrometry (LC–MS/MS) to facilitate comprehensive and unbiased detection of low-abundance proteins (LAPs). Through profiling of plasma proteomes from 42 individuals with MCI and 13 cognitively normal controls (NC), we identified 35 differentially expressed proteins (DEPs), of which four prioritized candidates were significantly correlated with Mini-Mental State Examination (MMSE) scores. Composite panels of candidate proteins showed potential to discriminate MCI, APOE4-carrier MCI, and amnestic MCI subtypes cases from NC, potentially providing insight into pathophysiological mechanisms underlying cognitive impairment. These findings highlight novel blood-based protein candidates uncovered by overcoming key limitations of conventional plasma proteomics, with potential to support MCI diagnosis.