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Early screening, particularly in blood plasma, has been demonstrated as a promising approach to the diagnosis and prevention of AD. In addition, metabolic dysfunction has been demonstrated to be closely related to AD, which might be reflected in the whole blood transcriptome. Hence, we hypothesized that the establishment of a diagnostic model based on the metabolic signatures of blood is a workable strategy. To that end, we initially constructed metabolic pathway pairwise (MPP) signatures to characterize the interplay among metabolic pathways. Then, a series of bioinformatic methodologies, e.g., differential expression analysis, functional enrichment analysis, network analysis, etc., were used to investigate the molecular mechanism behind AD. Moreover, an unsupervised clustering analysis based on the MPP signature profile via the Non-Negative Matrix Factorization (NMF) algorithm was utilized to stratify AD patients. Finally, aimed at distinguishing AD patients from non-AD groups, a metabolic pathway-pairwise scoring system (MPPSS) was established using multi-machine learning methods. As a result, many metabolic pathways correlated to AD were disclosed, including oxidative phosphorylation, fatty acid biosynthesis, etc. NMF clustering analysis divided AD patients into two subgroups (S1 and S2), which exhibit distinct activities of metabolism and immunity. Typically, oxidative phosphorylation in S2 exhibits a lower activity than that in S1 and non-AD group, suggesting the patients in S2 might possess a more compromised brain metabolism. Additionally, immune infiltration analysis showed that the patients in S2 might have phenomena of immune suppression compared with S1 and the non-AD group. These findings indicated that S2 probably has a more severe progression of AD. Finally, MPPSS could achieve an AUC of 0.73 (95%CI: 0.70, 0.77) in the training dataset, 0.71 (95%CI: 0.65, 0.77) in the testing dataset, and an AUC of 0.99 (95%CI: 0.96, 1.00) in one external validation dataset. Overall, our study successfully established a novel metabolism-based scoring system for AD diagnosis using the blood transcriptome and provided new insight into the molecular mechanism of metabolic dysfunction implicated in AD.<\/jats:p>","DOI":"10.3390\/genes14061285","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T01:31:14Z","timestamp":1687138274000},"page":"1285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Metabolic Pathway Pairwise-Based Signature as a Potential Non-Invasive Diagnostic Marker in Alzheimer\u2019s Disease Patients"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7347-3197","authenticated-orcid":false,"given":"Yunwen","family":"Feng","sequence":"first","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1343-0231","authenticated-orcid":false,"given":"Xingyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2486-7931","authenticated-orcid":false,"given":"Xiaohua Douglas","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biostatitics, College of Public Health, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7092-7587","authenticated-orcid":false,"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jalz.2012.02.001","article-title":"2012 Alzheimer\u2019s disease facts and figures","volume":"8","year":"2012","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s11910-020-01090-y","article-title":"Early-Onset Alzheimer\u2019s Disease: What Is Missing in Research?","volume":"21","author":"Ayodele","year":"2021","journal-title":"Curr. 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