{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T23:38:05Z","timestamp":1783640285593,"version":"3.55.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer\u2019s disease (AD), and thus identifying who among the increasing T2DM populations may develop into AD is important for early intervention. By using TMT-labeling coupled high-throughput mass spectrometry, we conducted a comprehensive plasma proteomic analysis in none-T2DM people (Ctrl, <jats:italic>n<\/jats:italic> = 30), and the age-\/sex-matched T2DM patients with mild cognitive impairment (T2DM-MCI, <jats:italic>n<\/jats:italic> = 30) or T2DM without MCI (T2DM-nMCI, <jats:italic>n<\/jats:italic> = 25). The candidate biomarkers identified by proteomics and bioinformatics analyses were verified by ELISA, and their diagnostic capabilities were evaluated with machine learning. A total of 53 differentially expressed proteins (DEPs) were identified in T2DM-MCI compared with T2DM-nMCI patients. These DEPs were significantly enriched in multiple biological processes, such as amyloid neuropathies, CNS disorders, and metabolic acidosis. Among the DEPs, alpha-1-antitrypsin (SERPINA1), major viral protein (PRNP), and valosin-containing protein (VCP) showed strong correlation with AD high-risk genes APP, MAPT, APOE, PSEN1, and PSEN2. Also, the levels of PP2A cancer inhibitor (CIP2A), PRNP, corticotropin-releasing factor-binding protein (CRHBP) were significantly increased, while the level of VCP was decreased in T2DM-MCI patients compared with that of the T2DM-nMCI, and these changes were correlated with the Mini-Mental State Examination (MMSE) score. Further machine learning data showed that increases in PRNP, CRHBP, VCP, and rGSK-3\u03b2(T\/S9) (ratio of total to serine-9-phosphorylated glycogen synthase kinase-3\u03b2) had the greatest power to identify mild cognitive decline in T2DM patients.<\/jats:p>","DOI":"10.3389\/fcell.2022.818141","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T07:25:27Z","timestamp":1669274727000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Discovering new peripheral plasma biomarkers to identify cognitive decline in type 2 diabetes"],"prefix":"10.3389","volume":"10","author":[{"given":"Haitao","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Zhi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1111\/j.1365-2125.2010.03830.x","article-title":"Diabetes mellitus and Alzheimer's disease: Shared pathology and treatment?","volume":"71","author":"Akter","year":"2011","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the national Institute on aging-alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease","volume":"7","author":"Albert","year":"2011","journal-title":"Alzheimers Dement."},{"key":"B3","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1074\/mcp.r200007-mcp200","article-title":"The human plasma proteome: History, character, and diagnostic prospects","volume":"1","author":"Anderson","year":"2002","journal-title":"Mol. Cell. Proteomics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e9356","DOI":"10.15252\/msb.20199356","article-title":"Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease","volume":"16","author":"Bader","year":"2020","journal-title":"Mol. Syst. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1046\/j.1471-4159.1997.68052053.x","article-title":"Corticotropin-releasing factor (CRF), CRF-binding protein (CRF-BP), and CRF\/CRF-BP complex in Alzheimer's disease and control postmortem human brain","volume":"68","author":"Behan","year":"1997","journal-title":"J. Neurochem."},{"key":"B6","article-title":"Fructose-1,6-Bisphosphatase deficiency","volume-title":"GeneReviews","author":"Bijarnia-Mahay","year":"1993"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3067","DOI":"10.1001\/jama.1985.03360210083036","article-title":"Corticotropin-releasing factor-like immunoreactivity in senile dementia of the Alzheimer type. Reduced cortical and striatal concentrations","volume":"254","author":"Bissette","year":"1985","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s10545-010-9053-2","article-title":"The biochemical basis of hereditary fructose intolerance","volume":"33","author":"Bouteldja","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.diabres.2018.11.013","article-title":"Diabetic ketoacidosis further increases risk of Alzheimer's disease in patients with type 2 diabetes","volume":"147","author":"Chen","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B10","doi-asserted-by":"publisher","first-page":"215 e219","DOI":"10.1016\/j.neurobiolaging.2016.09.017","article-title":"Lack of association of mortalin (HSPA9) and other mitochondria-related genes with risk of Parkinson's and Alzheimer's diseases","volume":"49","author":"Chung","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"B11","doi-asserted-by":"publisher","first-page":"eaay8826","DOI":"10.1126\/science.aay8826","article-title":"Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau","volume":"370","author":"Darwich","year":"2020","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/med.21440","article-title":"Bridging type 2 diabetes and Alzheimer's disease: Assembling the puzzle pieces in the quest for the molecules with therapeutic and preventive potential","volume":"38","author":"De Matos","year":"2018","journal-title":"Med. Res. Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1111\/jnc.15166","article-title":"Alzheimer's disease and type 2 diabetes mellitus: A systematic review of proteomic studies","volume":"156","author":"Diniz Pereira","year":"2021","journal-title":"J. Neurochem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1080\/15384101.2017.1417707","article-title":"Mitochondrial complex III Rieske Fe-S protein processing and assembly","volume":"17","author":"Fernandez-Vizarra","year":"2018","journal-title":"Cell Cycle"},{"key":"B15","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"Mini-mental state\". A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatr. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nrneurol.2009.215","article-title":"The clinical use of structural MRI in Alzheimer disease","volume":"6","author":"Frisoni","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"6367","DOI":"10.1523\/JNEUROSCI.0395-10.2010","article-title":"Memory impairment in transgenic Alzheimer mice requires cellular prion protein","volume":"30","author":"Gimbel","year":"2010","journal-title":"J. Neurosci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1038\/d41586-018-05717-6","article-title":"Alzheimer's disease","volume":"559","author":"Hodson","year":"2018","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1210\/er.2008-0028","article-title":"Unraveling insulin-like growth factor binding protein-3 actions in human disease","volume":"30","author":"Jogie-Brahim","year":"2009","journal-title":"Endocr. Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1016\/S0140-6736(13)62154-6","article-title":"Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future","volume":"383","author":"Kahn","year":"2014","journal-title":"Lancet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1042\/BST0360105","article-title":"Roles of VCP in human neurodegenerative disorders","volume":"36","author":"Kakizuka","year":"2008","journal-title":"Biochem. Soc. Trans."},{"key":"B22","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/j.1365-2672.2012.05310.x","article-title":"Prolidase function in proline metabolism and its medical and biotechnological applications","volume":"113","author":"Kitchener","year":"2012","journal-title":"J. Appl. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2990","DOI":"10.1039\/c6cp07145g","article-title":"Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: Consideration as a possible model","volume":"19","author":"Kouza","year":"2017","journal-title":"Phys. Chem. Chem. Phys."},{"key":"B24","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1212\/wnl.37.3.535","article-title":"Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH) and corticotropin (ACTH) are reduced in patients with Alzheimer's disease","volume":"37","author":"May","year":"1987","journal-title":"Neurology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer's disease: Recommendations from the national Institute on aging-alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease","volume":"7","author":"Mckhann","year":"2011","journal-title":"Alzheimers Dement."},{"key":"B26","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/ncb2407","article-title":"Emerging functions of the VCP\/p97 AAA-ATPase in the ubiquitin system","volume":"14","author":"Meyer","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/nature25456","article-title":"High performance plasma amyloid-beta biomarkers for Alzheimer's disease","volume":"554","author":"Nakamura","year":"2018","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1750-1326-4-35","article-title":"Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells","volume":"4","author":"Nakamura","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1038\/s41380-019-0602-2","article-title":"Blood biomarkers for memory: Toward early detection of risk for alzheimer disease, pharmacogenomics, and repurposed drugs","volume":"25","author":"Niculescu","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"B30","doi-asserted-by":"publisher","first-page":"269","DOI":"10.5001\/omj.2012.68","article-title":"Type 2 diabetes mellitus: A review of current trends","volume":"27","author":"Olokoba","year":"2012","journal-title":"Oman Med. J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1001\/archneurol.2009.266","article-title":"Mild cognitive impairment: Ten years later","volume":"66","author":"Petersen","year":"2009","journal-title":"Arch. Neurol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1212\/wnl.56.9.1133","article-title":"Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review). Report of the quality standards subcommittee of the American academy of neurology","volume":"56","author":"Petersen","year":"2001","journal-title":"Neurology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"25457","DOI":"10.1074\/jbc.M603469200","article-title":"The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation","volume":"281","author":"Plattner","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ejrad.2017.07.014","article-title":"The diagnostic value of FDG and amyloid PET in Alzheimer's disease-A systematic review","volume":"94","author":"Rice","year":"2017","journal-title":"Eur. J. Radiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"9207","DOI":"10.1523\/JNEUROSCI.0722-17.2017","article-title":"Conditional deletion of prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer's disease","volume":"37","author":"Salazar","year":"2017","journal-title":"J. Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.celrep.2018.06.009","article-title":"CIP2A causes tau\/APP phosphorylation, synaptopathy, and memory deficits in Alzheimer's disease","volume":"24","author":"Shentu","year":"2018","journal-title":"Cell Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1016\/j.immuni.2020.10.008","article-title":"Plasma proteomics identify biomarkers and pathogenesis of COVID-19","volume":"53","author":"Shu","year":"2020","journal-title":"Immunity"},{"key":"B38","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1016\/j.biopha.2017.08.146","article-title":"The role of CIP2A in cancer: A review and update","volume":"96","author":"Soofiyani","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1007\/s10571-020-00796-4","article-title":"Caveolin: A new Link between diabetes and AD","volume":"40","author":"Surguchov","year":"2020","journal-title":"Cell. Mol. Neurobiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.2147\/CIA.S48926","article-title":"Type 2 diabetes as a risk factor for cognitive impairment: Current insights","volume":"9","author":"Umegaki","year":"2014","journal-title":"Clin. Interv. Aging"},{"key":"B41","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/s41398-019-0581-8","article-title":"Corticotropin releasing factor-binding protein (CRF-BP) as a potential new therapeutic target in Alzheimer's disease and stress disorders","volume":"9","author":"Vandael","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"B42","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13024-020-00384-6","article-title":"Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer's disease","volume":"15","author":"Wang","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"B43","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/S1474-4422(16)00062-4","article-title":"Defeating Alzheimer's disease and other dementias: A priority for European science and society","volume":"15","author":"Winblad","year":"2016","journal-title":"Lancet. Neurol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Wisniewski","year":"2009","journal-title":"Nat. Methods"},{"key":"B45","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.ebiom.2016.02.014","article-title":"Biomarkers for early diagnostic of mild cognitive impairment in type-2 diabetes patients: A multicentre, retrospective, nested case-control study","volume":"5","author":"Xu","year":"2016","journal-title":"EBioMedicine"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e24442","DOI":"10.1371\/journal.pone.0024442","article-title":"A systematic analysis of eluted fraction of plasma post immunoaffinity depletion: Implications in biomarker discovery","volume":"6","author":"Yadav","year":"2011","journal-title":"PLoS One"},{"key":"B47","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.neuropharm.2017.10.028","article-title":"Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity","volume":"128","author":"Yi","year":"2018","journal-title":"Neuropharmacology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"784","DOI":"10.3390\/biom11060784","article-title":"Harnessing the physiological functions of cellular prion protein in the kidneys: Applications for treating renal diseases","volume":"11","author":"Yoon","year":"2021","journal-title":"Biomolecules"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e13358","DOI":"10.1111\/acel.13358","article-title":"Platelet biomarkers for a descending cognitive function: A proteomic approach","volume":"20","author":"Yu","year":"2021","journal-title":"Aging Cell"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.818141\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T07:25:30Z","timestamp":1669274730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.818141\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,24]]},"references-count":49,"alternative-id":["10.3389\/fcell.2022.818141"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.818141","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,24]]},"article-number":"818141"}}