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At present, Alzheimer\u2019s disease (AD) lacks effective treatment means, and early diagnosis and intervention are the keys to treatment. Therefore, for mild cognitive impairment (MCI) and AD patients, blood sample analysis using the 4D nonstandard (label-free) proteomic in-depth quantitative analysis, looking for specific protein marker expression differences, is important. These marker levels change as AD progresses, and the analysis of these biomarkers changes with this method, which has the potential to show the degree of disease progression and can be used for the diagnosis and preventive treatment of MCI and AD. <jats:italic>Materials and Methods<\/jats:italic>. Patients were recruited according to the inclusion and exclusion criteria and divided into three groups according to scale scores. Elderly patients diagnosed with AD were selected as the AD group (<jats:italic>n<\/jats:italic>\u2009=\u20099). Patients diagnosed with MCI were classified into the MCI group (<jats:italic>n<\/jats:italic>\u2009=\u200910). Cognitively healthy elderly patients were included in the normal cognition control group (<jats:italic>n<\/jats:italic>\u2009=\u200910). Patients\u2019 blood samples were used for 4D label-free proteomic in-depth quantitative analysis to identify potential blood biomarkers. The sample size of each group was expanded (<jats:italic>n<\/jats:italic>\u2009=\u200930), and the selected biomarkers were verified by enzyme-linked immunosorbent assay (ELISA) to verify the accuracy of the proteomic prediction. <jats:italic>Results<\/jats:italic>. Six specific blood markers, namely, APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8, were detected by 4D label-free proteomic quantitative analysis. These markers showed a statistically significant upregulation trend in the MCI and AD groups compared with the normal cognition control group (<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\"><mml:mi>P<\/mml:mi><mml:mo>&lt;<\/mml:mo><mml:mn>0.05<\/mml:mn><\/mml:math>). ELISA results showed that the levels of these six proteins in the MCI group were significantly higher than those in the normal cognition control group, and the levels of these six proteins in the AD group were significantly higher than those in the MCI group (<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\"><mml:mi>P<\/mml:mi><mml:mo>&lt;<\/mml:mo><mml:mn>0.05<\/mml:mn><\/mml:math>). <jats:italic>Conclusion<\/jats:italic>. The plasma levels of APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8 in cognitively healthy elderly patients and patients with MCI and AD were significantly different and, more importantly, showed a trend of increasing expression. These results indicate that these six human plasma markers have important diagnostic and therapeutic potential in the identification of cognitive impairment and have value for in-depth research and clinical application.<\/jats:p>","DOI":"10.1155\/2024\/7709277","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T00:35:09Z","timestamp":1716856509000},"page":"1-23","source":"Crossref","is-referenced-by-count":6,"title":["What Are the Reliable Plasma Biomarkers for Mild Cognitive Impairment? 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