{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:43:05Z","timestamp":1792093385691,"version":"4.4.0"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic\u00a0models. We predicted microbial formate as well as other microbial metabolites, which could alter urine formate production in the host-microbiome personalised models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.<\/jats:p>","DOI":"10.1038\/s41598-024-55960-3","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T06:13:09Z","timestamp":1710310389000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"14","author":[{"given":"Filippo","family":"Martinelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almut","family":"Heinken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Kristin","family":"Henning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Ulmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Hensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Asthana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Budde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne D.","family":"Engelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrbod","family":"Estaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-J\u00f6rgen","family":"Grabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margo B.","family":"Heston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sterling","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabi","family":"Kastenm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Martino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico E.","family":"Rey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Kilimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olive","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eike Jakob","family":"Spruth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Fliessbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Wiltfang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzel","family":"Glanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Buerger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Janowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Laske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias H.","family":"Munk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Spottke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Nauck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Teipel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Knight","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima F.","family":"Kaddurah-Daouk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara B.","family":"Bendlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Hertel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Thiele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"55960_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207481","author":"M Ricci","year":"2020","unstructured":"Ricci, M., Cimini, A., Chiaravalloti, A., Filippi, L. & Schillaci, O. Positron emission tomography (PET) and neuroimaging in the personalized approach to neurodegenerative causes of dementia. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms21207481 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"55960_CR2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","volume":"7","author":"DS Knopman","year":"2021","unstructured":"Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Primers 7, 33. https:\/\/doi.org\/10.1038\/s41572-021-00269-y (2021).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"55960_CR3","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1590\/S1980-57642010DN40400003","volume":"4","author":"DM Castro","year":"2010","unstructured":"Castro, D. M., Dillon, C., Machnicki, G. & Allegri, R. F. The economic cost of Alzheimer\u2019s disease: Family or public health burden?. Dement. Neuropsychol. 4, 262\u2013267. https:\/\/doi.org\/10.1590\/S1980-57642010DN40400003 (2010).","journal-title":"Dement. Neuropsychol."},{"key":"55960_CR4","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1016\/j.jalz.2017.01.020","volume":"13","author":"JB Toledo","year":"2017","unstructured":"Toledo, J. B. et al. Metabolic network failures in Alzheimer\u2019s disease: A biochemical road map. Alzheimers Dement. 13, 965\u2013984. https:\/\/doi.org\/10.1016\/j.jalz.2017.01.020 (2017).","journal-title":"Alzheimers Dement."},{"key":"55960_CR5","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1056\/NEJMra1600266","volume":"375","author":"SV Lynch","year":"2016","unstructured":"Lynch, S. V. & Pedersen, O. The human intestinal microbiome in health and disease. N. Engl. J. Med. 375, 2369\u20132379. https:\/\/doi.org\/10.1056\/NEJMra1600266 (2016).","journal-title":"N. Engl. J. Med."},{"key":"55960_CR6","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.immuni.2020.07.015","volume":"53","author":"M Alexander","year":"2020","unstructured":"Alexander, M. & Turnbaugh, P. J. deconstructing mechanisms of diet-microbiome-immune interactions. Immunity 53, 264\u2013276. https:\/\/doi.org\/10.1016\/j.immuni.2020.07.015 (2020).","journal-title":"Immunity"},{"key":"55960_CR7","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1152\/physrev.00018.2018","volume":"99","author":"JF Cryan","year":"2019","unstructured":"Cryan, J. F. et al. The microbiota-gut-brain axis. Physiol. Rev. 99, 1877\u20132013. https:\/\/doi.org\/10.1152\/physrev.00018.2018 (2019).","journal-title":"Physiol. Rev."},{"key":"55960_CR8","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.coph.2019.08.004","volume":"48","author":"CE Gheorghe","year":"2019","unstructured":"Gheorghe, C. E. et al. Focus on the essentials: Tryptophan metabolism and the microbiome-gut-brain axis. Curr. Opin. Pharmacol. 48, 137\u2013145. https:\/\/doi.org\/10.1016\/j.coph.2019.08.004 (2019).","journal-title":"Curr. Opin. Pharmacol."},{"key":"55960_CR9","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15571","author":"L Bonfili","year":"2020","unstructured":"Bonfili, L. et al. Microbiota modulation as preventative and therapeutic approach in Alzheimer\u2019s disease. FEBS J. https:\/\/doi.org\/10.1111\/febs.15571 (2020).","journal-title":"FEBS J."},{"key":"55960_CR10","doi-asserted-by":"publisher","first-page":"110112","DOI":"10.1016\/j.pnpbp.2020.110112","volume":"106","author":"D Goyal","year":"2021","unstructured":"Goyal, D., Ali, S. A. & Singh, R. K. Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer\u2019s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 106, 110112. https:\/\/doi.org\/10.1016\/j.pnpbp.2020.110112 (2021).","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"55960_CR11","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.jalz.2018.07.217","volume":"15","author":"S MahmoudianDehkordi","year":"2019","unstructured":"MahmoudianDehkordi, S. et al. Altered bile acid profile associates with cognitive impairment in Alzheimer\u2019s disease-An emerging role for gut microbiome. Alzheimers Dement. 15, 76\u201392. https:\/\/doi.org\/10.1016\/j.jalz.2018.07.217 (2019).","journal-title":"Alzheimers Dement."},{"key":"55960_CR12","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.jalz.2018.08.012","volume":"15","author":"K Nho","year":"2019","unstructured":"Nho, K. et al. Altered bile acid profile in mild cognitive impairment and Alzheimer\u2019s disease: Relationship to neuroimaging and CSF biomarkers. Alzheimers Dement. 15, 232\u2013244. https:\/\/doi.org\/10.1016\/j.jalz.2018.08.012 (2019).","journal-title":"Alzheimers Dement."},{"key":"55960_CR13","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.molmet.2019.05.012","volume":"33","author":"M Pietzke","year":"2020","unstructured":"Pietzke, M., Meiser, J. & Vazquez, A. Formate metabolism in health and disease. Mol. Metab. 33, 23\u201337. https:\/\/doi.org\/10.1016\/j.molmet.2019.05.012 (2020).","journal-title":"Mol. Metab."},{"key":"55960_CR14","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.1046066","author":"Y Wang","year":"2022","unstructured":"Wang, Y. et al. Systematic evaluation of urinary formic acid as a new potential biomarker for Alzheimer\u2019s disease. Front. Aging Neurosci. https:\/\/doi.org\/10.3389\/fnagi.2022.1046066 (2022).","journal-title":"Front. Aging Neurosci."},{"key":"55960_CR15","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9781139854610","volume-title":"Systems Biology: Constraint-based Reconstruction and Analysis","author":"B\u00d8 Palsson","year":"2015","unstructured":"Palsson, B. \u00d8. Systems Biology: Constraint-based Reconstruction and Analysis (Cambridge University Press, 2015)."},{"key":"55960_CR16","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nprot.2009.203","volume":"5","author":"I Thiele","year":"2010","unstructured":"Thiele, I. & Palsson, B. \u00d8. A protocol for generating a high-quality genome-scale metabolic reconstruction. Nat. Protocols 5, 93\u2013121 (2010).","journal-title":"Nat. Protocols"},{"key":"55960_CR17","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/nbt.1614","volume":"28","author":"JD Orth","year":"2010","unstructured":"Orth, J. D., Thiele, I. & Palsson, B. O. What is flux balance analysis?. Nat. Biotechnol. 28, 245\u2013248 (2010).","journal-title":"Nat. Biotechnol."},{"key":"55960_CR18","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nbt.3703","volume":"35","author":"S Magnusdottir","year":"2017","unstructured":"Magnusdottir, S. et al. Generation of genome-scale metabolic reconstructions for 773 members of the human gut microbiota. Nat. Biotechnol. 35, 81\u201389. https:\/\/doi.org\/10.1038\/nbt.3703 (2017).","journal-title":"Nat. Biotechnol."},{"key":"55960_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01628-0","author":"A Heinken","year":"2023","unstructured":"Heinken, A. et al. Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine. Nat. Biotechnol. https:\/\/doi.org\/10.1038\/s41587-022-01628-0 (2023).","journal-title":"Nat. Biotechnol."},{"key":"55960_CR20","doi-asserted-by":"publisher","DOI":"10.1101\/2023.10.02.560573","author":"A Heinken","year":"2023","unstructured":"Heinken, A. et al. APOLLO: A genome-scale metabolic reconstruction resource of 247,092 diverse human microbes spanning multiple continents, age groups, and body sites. bioRxiv https:\/\/doi.org\/10.1101\/2023.10.02.560573 (2023).","journal-title":"bioRxiv"},{"key":"55960_CR21","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty941","author":"F Baldini","year":"2018","unstructured":"Baldini, F. et al. The microbiome modeling toolbox: From microbial interactions to personalized microbial communities. Bioinformatics https:\/\/doi.org\/10.1093\/bioinformatics\/bty941 (2018).","journal-title":"Bioinformatics"},{"key":"55960_CR22","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1093\/bioinformatics\/btac082","volume":"38","author":"A Heinken","year":"2022","unstructured":"Heinken, A. & Thiele, I. Microbiome Modelling Toolbox 2.0: Efficient, tractable modelling of microbiome communities. Bioinformatics 38, 2367\u20132368. https:\/\/doi.org\/10.1093\/bioinformatics\/btac082 (2022).","journal-title":"Bioinformatics"},{"key":"55960_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2021.1915673","volume":"13","author":"J Hertel","year":"2021","unstructured":"Hertel, J., Heinken, A., Martinelli, F. & Thiele, I. Integration of constraint-based modeling with fecal metabolomics reveals large deleterious effects of Fusobacterium spp. on community butyrate production. Gut Microbes 13, 1\u201323. https:\/\/doi.org\/10.1080\/19490976.2021.1915673 (2021).","journal-title":"Gut Microbes"},{"key":"55960_CR24","doi-asserted-by":"publisher","first-page":"e8982","DOI":"10.15252\/msb.20198982","volume":"16","author":"I Thiele","year":"2020","unstructured":"Thiele, I. et al. Personalized whole-body models integrate metabolism, physiology, and the gut microbiome. Mol. Syst. Biol. 16, e8982. https:\/\/doi.org\/10.15252\/msb.20198982 (2020).","journal-title":"Mol. Syst. Biol."},{"key":"55960_CR25","doi-asserted-by":"publisher","first-page":"2226921","DOI":"10.1080\/19490976.2023.2226921","volume":"15","author":"A Basile","year":"2023","unstructured":"Basile, A. et al. Longitudinal flux balance analyses of a patient with episodic colonic inflammation reveals microbiome metabolic dynamics. Gut Microbes 15, 2226921. https:\/\/doi.org\/10.1080\/19490976.2023.2226921 (2023).","journal-title":"Gut Microbes"},{"key":"55960_CR26","doi-asserted-by":"publisher","first-page":"4098","DOI":"10.1016\/j.csbj.2022.07.019","volume":"20","author":"I Thiele","year":"2022","unstructured":"Thiele, I. & Fleming, R. M. T. Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication. Comput. Struct. Biotechnol. J. 20, 4098\u20134109. https:\/\/doi.org\/10.1016\/j.csbj.2022.07.019 (2022).","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"55960_CR27","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13195-017-0314-2","volume":"10","author":"F Jessen","year":"2018","unstructured":"Jessen, F. et al. Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer\u2019s disease (DELCODE). Alzheimers Res. Ther. 10, 15. https:\/\/doi.org\/10.1186\/s13195-017-0314-2 (2018).","journal-title":"Alzheimers Res. Ther."},{"key":"55960_CR28","doi-asserted-by":"publisher","first-page":"13537","DOI":"10.1038\/s41598-017-13601-y","volume":"7","author":"NM Vogt","year":"2017","unstructured":"Vogt, N. M. et al. Gut microbiome alterations in Alzheimer\u2019s disease. Sci. Rep. 7, 13537. https:\/\/doi.org\/10.1038\/s41598-017-13601-y (2017).","journal-title":"Sci. Rep."},{"key":"55960_CR29","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1212\/wnl.43.8.1467","volume":"43","author":"AM Saunders","year":"1993","unstructured":"Saunders, A. M. et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer\u2019s disease. Neurology 43, 1467\u20131472. https:\/\/doi.org\/10.1212\/wnl.43.8.1467 (1993).","journal-title":"Neurology"},{"key":"55960_CR30","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1001\/jamaneurol.2014.1491","volume":"71","author":"AC Naj","year":"2014","unstructured":"Naj, A. C. et al. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: A genome-wide association study. JAMA Neurol. 71, 1394\u20131404. https:\/\/doi.org\/10.1001\/jamaneurol.2014.1491 (2014).","journal-title":"JAMA Neurol."},{"key":"55960_CR31","doi-asserted-by":"publisher","first-page":"e00167","DOI":"10.1128\/msystems.00167-22","volume":"7","author":"Q Zhu","year":"2022","unstructured":"Zhu, Q. et al. Phylogeny-aware analysis of metagenome community ecology based on matched reference genomes while bypassing taxonomy. mSystems 7, e00167-e122. https:\/\/doi.org\/10.1128\/msystems.00167-22 (2022).","journal-title":"mSystems"},{"key":"55960_CR32","doi-asserted-by":"publisher","first-page":"5477","DOI":"10.1038\/s41467-019-13443-4","volume":"10","author":"Q Zhu","year":"2019","unstructured":"Zhu, Q. et al. Phylogenomics of 10,575 genomes reveals evolutionary proximity between domains Bacteria and Archaea. Nat. Commun. 10, 5477. https:\/\/doi.org\/10.1038\/s41467-019-13443-4 (2019).","journal-title":"Nat. Commun."},{"key":"55960_CR33","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/s41592-018-0141-9","volume":"15","author":"A Gonzalez","year":"2018","unstructured":"Gonzalez, A. et al. Qiita: Rapid, web-enabled microbiome meta-analysis. Nat. Methods 15, 796\u2013798. https:\/\/doi.org\/10.1038\/s41592-018-0141-9 (2018).","journal-title":"Nat. Methods"},{"key":"55960_CR34","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1146\/annurev-nutr-071715-050738","volume":"36","author":"ME Brosnan","year":"2016","unstructured":"Brosnan, M. E. & Brosnan, J. T. Formate: The neglected member of one-carbon metabolism. Annu. Rev. Nutr. 36, 369\u2013388. https:\/\/doi.org\/10.1146\/annurev-nutr-071715-050738 (2016).","journal-title":"Annu. Rev. Nutr."},{"key":"55960_CR35","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.aca.2020.10.038","volume":"1141","author":"MA W\u00f6rheide","year":"2021","unstructured":"W\u00f6rheide, M. A., Krumsiek, J., Kastenm\u00fcller, G. & Arnold, M. Multi-omics integration in biomedical research: A metabolomics-centric review. Anal. Chim. Acta 1141, 144\u2013162. https:\/\/doi.org\/10.1016\/j.aca.2020.10.038 (2021).","journal-title":"Anal. Chim. Acta"},{"key":"55960_CR36","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.719159","author":"Y Watanabe","year":"2021","unstructured":"Watanabe, Y. et al. Alterations in glycerolipid and fatty acid metabolic pathways in Alzheimer\u2019s disease identified by urinary metabolic profiling: A pilot study. Front. Neurol. https:\/\/doi.org\/10.3389\/fneur.2021.719159 (2021).","journal-title":"Front. Neurol."},{"key":"55960_CR37","doi-asserted-by":"publisher","DOI":"10.3390\/metabo10090357","author":"A Yilmaz","year":"2020","unstructured":"Yilmaz, A. et al. Targeted metabolic profiling of urine highlights a potential biomarker panel for the diagnosis of Alzheimer\u2019s disease and mild cognitive impairment: A pilot study. Metabolites https:\/\/doi.org\/10.3390\/metabo10090357 (2020).","journal-title":"Metabolites"},{"key":"55960_CR38","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1080\/15298668791385787","volume":"48","author":"MF Boeniger","year":"1987","unstructured":"Boeniger, M. F. Formate in urine as a biological indicator of formaldehyde exposure: A review. Am. Ind. Hyg. Assoc. J. 48, 900\u2013908. https:\/\/doi.org\/10.1080\/15298668791385787 (1987).","journal-title":"Am. Ind. Hyg. Assoc. J."},{"key":"55960_CR39","doi-asserted-by":"publisher","first-page":"e12064","DOI":"10.1002\/dad2.12064","volume":"12","author":"I Hajjar","year":"2020","unstructured":"Hajjar, I., Liu, C., Jones, D. P. & Uppal, K. Untargeted metabolomics reveal dysregulations in sugar, methionine, and tyrosine pathways in the prodromal state of AD. Alzheimer\u2019s Dement. 12, e12064. https:\/\/doi.org\/10.1002\/dad2.12064 (2020).","journal-title":"Alzheimer's Dement."},{"key":"55960_CR40","doi-asserted-by":"publisher","first-page":"e244","DOI":"10.1038\/tp.2013.18","volume":"3","author":"R Kaddurah-Daouk","year":"2013","unstructured":"Kaddurah-Daouk, R. et al. Alterations in metabolic pathways and networks in Alzheimer\u2019s disease. Transl. Psychiatry 3, e244. https:\/\/doi.org\/10.1038\/tp.2013.18 (2013).","journal-title":"Transl. Psychiatry"},{"key":"55960_CR41","doi-asserted-by":"publisher","first-page":"101800","DOI":"10.1016\/j.pneurobio.2020.101800","volume":"190","author":"M Maitre","year":"2020","unstructured":"Maitre, M., Klein, C., Patte-Mensah, C. & Mensah-Nyagan, A. G. Tryptophan metabolites modify brain A\u03b2 peptide degradation: A role in Alzheimer\u2019s disease?. Progr. Neurobiol. 190, 101800. https:\/\/doi.org\/10.1016\/j.pneurobio.2020.101800 (2020).","journal-title":"Progr. Neurobiol."},{"key":"55960_CR42","doi-asserted-by":"publisher","first-page":"S405","DOI":"10.3233\/jad-179911","volume":"64","author":"JR Clarke","year":"2018","unstructured":"Clarke, J. R., Ribeiro, F. C., Frozza, R. L., De Felice, F. G. & Lourenco, M. V. Metabolic dysfunction in Alzheimer\u2019s disease: From basic neurobiology to clinical approaches. J. Alzheimer\u2019s Dis. 64, S405-s426. https:\/\/doi.org\/10.3233\/jad-179911 (2018).","journal-title":"J. Alzheimer's Dis."},{"key":"55960_CR43","doi-asserted-by":"publisher","first-page":"5472792","DOI":"10.1155\/2017\/5472792","volume":"2017","author":"JW Griffin","year":"2017","unstructured":"Griffin, J. W. & Bradshaw, P. C. Amino acid catabolism in alzheimer\u2019s disease brain: Friend or foe?. Oxid. Med. Cell. Longev. 2017, 5472792. https:\/\/doi.org\/10.1155\/2017\/5472792 (2017).","journal-title":"Oxid. Med. Cell. Longev."},{"key":"55960_CR44","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.neuropharm.2016.08.003","volume":"112","author":"R Schwarcz","year":"2017","unstructured":"Schwarcz, R. & Stone, T. W. The kynurenine pathway and the brain: Challenges, controversies and promises. Neuropharmacology 112, 237\u2013247. https:\/\/doi.org\/10.1016\/j.neuropharm.2016.08.003 (2017).","journal-title":"Neuropharmacology"},{"key":"55960_CR45","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1176\/appi.ajp.157.4.638","volume":"157","author":"RJ Porter","year":"2000","unstructured":"Porter, R. J. et al. Cognitive deficit induced by acute tryptophan depletion in patients with Alzheimer\u2019s disease. Am. J. Psychiatry 157, 638\u2013640. https:\/\/doi.org\/10.1176\/appi.ajp.157.4.638 (2000).","journal-title":"Am. J. Psychiatry"},{"key":"55960_CR46","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13195-020-00741-z","volume":"13","author":"L Whiley","year":"2021","unstructured":"Whiley, L. et al. Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer\u2019s disease. Alzheimers Res. Ther. 13, 20. https:\/\/doi.org\/10.1186\/s13195-020-00741-z (2021).","journal-title":"Alzheimers Res. Ther."},{"key":"55960_CR47","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s13195-019-0551-7","volume":"11","author":"V van der Velpen","year":"2019","unstructured":"van der Velpen, V. et al. Systemic and central nervous system metabolic alterations in Alzheimer\u2019s disease. Alzheimer\u2019s Res. Ther. 11, 93. https:\/\/doi.org\/10.1186\/s13195-019-0551-7 (2019).","journal-title":"Alzheimer's Res. Ther."},{"key":"55960_CR48","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s40170-020-00228-3","volume":"8","author":"J Tait-Mulder","year":"2020","unstructured":"Tait-Mulder, J., Hodge, K., Sumpton, D., Zanivan, S. & Vazquez, A. The conversion of formate into purines stimulates mTORC1 leading to CAD-dependent activation of pyrimidine synthesis. Cancer Metab. 8, 20. https:\/\/doi.org\/10.1186\/s40170-020-00228-3 (2020).","journal-title":"Cancer Metab."},{"key":"55960_CR49","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.661198","author":"X Zhang","year":"2021","unstructured":"Zhang, X. et al. The association between folate and Alzheimer\u2019s disease: A systematic review and meta-analysis. Front. Neurosci. https:\/\/doi.org\/10.3389\/fnins.2021.661198 (2021).","journal-title":"Front. Neurosci."},{"key":"55960_CR50","doi-asserted-by":"publisher","first-page":"871","DOI":"10.3389\/fnins.2019.00871","volume":"13","author":"N Bergau","year":"2019","unstructured":"Bergau, N., Maul, S., Rujescu, D., Simm, A. & Navarrete Santos, A. Reduction of glycolysis intermediate concentrations in the cerebrospinal fluid of alzheimer\u2019s disease patients. Front. Neurosci. 13, 871. https:\/\/doi.org\/10.3389\/fnins.2019.00871 (2019).","journal-title":"Front. Neurosci."},{"key":"55960_CR51","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s13059-019-1730-3","volume":"20","author":"C Gu","year":"2019","unstructured":"Gu, C., Kim, G. B., Kim, W. J., Kim, H. U. & Lee, S. Y. Current status and applications of genome-scale metabolic models. Genome Biol. 20, 121. https:\/\/doi.org\/10.1186\/s13059-019-1730-3 (2019).","journal-title":"Genome Biol."},{"key":"55960_CR52","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/nbt.4072","volume":"36","author":"E Brunk","year":"2018","unstructured":"Brunk, E. et al. Recon3D enables a three-dimensional view of gene variation in human metabolism. Nat. Biotechnol. 36, 272\u2013281. https:\/\/doi.org\/10.1038\/nbt.4072 (2018).","journal-title":"Nat. Biotechnol."},{"key":"55960_CR53","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nbt.2488","volume":"31","author":"I Thiele","year":"2013","unstructured":"Thiele, I. et al. A community-driven global reconstruction of human metabolism. Nat. Biotechnol. 31, 419\u2013425. https:\/\/doi.org\/10.1038\/nbt.2488 (2013).","journal-title":"Nat. Biotechnol."},{"key":"55960_CR54","doi-asserted-by":"publisher","first-page":"3974","DOI":"10.1093\/bioinformatics\/btab622","volume":"37","author":"A Heinken","year":"2021","unstructured":"Heinken, A., Magn\u00fasd\u00f3ttir, S., Fleming, R. M. T. & Thiele, I. DEMETER: Efficient simultaneous curation of genome-scale reconstructions guided by experimental data and refined gene annotations. Bioinformatics 37, 3974\u20133975. https:\/\/doi.org\/10.1093\/bioinformatics\/btab622 (2021).","journal-title":"Bioinformatics"},{"key":"55960_CR55","doi-asserted-by":"publisher","first-page":"D631","DOI":"10.1093\/nar\/gky879","volume":"47","author":"LC Reimer","year":"2018","unstructured":"Reimer, L. C. et al. BacDive in 2019: Bacterial phenotypic data for High-throughput biodiversity analysis. Nucleic Acids Res. 47, D631\u2013D636. https:\/\/doi.org\/10.1093\/nar\/gky879 (2018).","journal-title":"Nucleic Acids Res."},{"key":"55960_CR56","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1016\/j.jalz.2014.01.001","volume":"10","author":"F Jessen","year":"2014","unstructured":"Jessen, F. et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer\u2019s disease. Alzheimers Dement. 10, 844\u2013852. https:\/\/doi.org\/10.1016\/j.jalz.2014.01.001 (2014).","journal-title":"Alzheimers Dement."},{"key":"55960_CR57","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","volume":"7","author":"MS Albert","year":"2011","unstructured":"Albert, M. S. et al. The diagnosis of mild cognitive impairment due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement. 7, 270\u2013279. https:\/\/doi.org\/10.1016\/j.jalz.2011.03.008 (2011).","journal-title":"Alzheimers Dement."},{"key":"55960_CR58","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","volume":"7","author":"GM McKhann","year":"2011","unstructured":"McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement. 7, 263\u2013269. https:\/\/doi.org\/10.1016\/j.jalz.2011.03.005 (2011).","journal-title":"Alzheimers Dement."},{"key":"55960_CR59","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1159\/000381308","volume":"4","author":"M Pietzner","year":"2015","unstructured":"Pietzner, M. et al. Urine metabolomics by (1)H-NMR spectroscopy indicates associations between serum 3,5\u2013T2 concentrations and intermediary metabolism in euthyroid humans. Eur. Thyroid J. 4, 92\u2013100. https:\/\/doi.org\/10.1159\/000381308 (2015).","journal-title":"Eur. Thyroid J."},{"key":"55960_CR60","doi-asserted-by":"publisher","first-page":"3856","DOI":"10.1210\/jc.2018-00999","volume":"103","author":"M Pietzner","year":"2018","unstructured":"Pietzner, M. et al. Hepatic steatosis is associated with adverse molecular signatures in subjects without diabetes. J. Clin. Endocrinol. Metab. 103, 3856\u20133868. https:\/\/doi.org\/10.1210\/jc.2018-00999 (2018).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"55960_CR61","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.aca.2018.07.068","volume":"1032","author":"J Hertel","year":"2018","unstructured":"Hertel, J. et al. Dilution correction for dynamically influenced urinary analyte data. Anal. Chim. Acta 1032, 18\u201331. https:\/\/doi.org\/10.1016\/j.aca.2018.07.068 (2018).","journal-title":"Anal. Chim. Acta"},{"key":"55960_CR62","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1097\/wad.0000000000000279","volume":"32","author":"L Besser","year":"2018","unstructured":"Besser, L. et al. Version 3 of the National Alzheimer\u2019s Coordinating Center\u2019s uniform data set. Alzheimer Dis. Assoc. Disord. 32, 351\u2013358. https:\/\/doi.org\/10.1097\/wad.0000000000000279 (2018).","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"55960_CR63","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.dadm.2017.11.007","volume":"10","author":"SC Johnson","year":"2018","unstructured":"Johnson, S. C. et al. The Wisconsin Registry for Alzheimer\u2019s Prevention: A review of findings and current directions. Alzheimer\u2019s Dement. 10, 130\u2013142. https:\/\/doi.org\/10.1016\/j.dadm.2017.11.007 (2018).","journal-title":"Alzheimer's Dement."},{"key":"55960_CR64","doi-asserted-by":"publisher","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","volume":"34","author":"S Chen","year":"2018","unstructured":"Chen, S., Zhou, Y., Chen, Y. & Gu, J. FASTP: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34, i884\u2013i890. https:\/\/doi.org\/10.1093\/bioinformatics\/bty560 (2018).","journal-title":"Bioinformatics"},{"key":"55960_CR65","doi-asserted-by":"publisher","first-page":"3094","DOI":"10.1093\/bioinformatics\/bty191","volume":"34","author":"H Li","year":"2018","unstructured":"Li, H. Minimap2: Pairwise alignment for nucleotide sequences. Bioinformatics 34, 3094\u20133100. https:\/\/doi.org\/10.1093\/bioinformatics\/bty191 (2018).","journal-title":"Bioinformatics"},{"key":"55960_CR66","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","volume":"9","author":"B Langmead","year":"2012","unstructured":"Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357\u2013359. https:\/\/doi.org\/10.1038\/nmeth.1923 (2012).","journal-title":"Nat. Methods"},{"key":"55960_CR67","doi-asserted-by":"publisher","first-page":"28","DOI":"10.4161\/gmic.22370","volume":"4","author":"A Heinken","year":"2013","unstructured":"Heinken, A., Sahoo, S., Fleming, R. M. & Thiele, I. Systems-level characterization of a host-microbe metabolic symbiosis in the mammalian gut. Gut Microbes 4, 28\u201340. https:\/\/doi.org\/10.4161\/gmic.22370 (2013).","journal-title":"Gut Microbes"},{"key":"55960_CR68","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1016\/j.bpj.2010.01.060","volume":"98","author":"I Thiele","year":"2010","unstructured":"Thiele, I., Fleming, R. M., Bordbar, A., Schellenberger, J. & Palsson, B. Functional characterization of alternate optimal solutions of Escherichia coli\u2019s transcriptional and translational machinery. Biophys. J. 98, 2072\u20132081. https:\/\/doi.org\/10.1016\/j.bpj.2010.01.060 (2010).","journal-title":"Biophys. J."},{"key":"55960_CR69","doi-asserted-by":"publisher","first-page":"D614","DOI":"10.1093\/nar\/gky992","volume":"47","author":"A Noronha","year":"2019","unstructured":"Noronha, A. et al. The Virtual Metabolic Human database: Integrating human and gut microbiome metabolism with nutrition and disease. Nucleic Acids Res. 47, D614\u2013D624. https:\/\/doi.org\/10.1093\/nar\/gky992 (2019).","journal-title":"Nucleic Acids Res."},{"key":"55960_CR70","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/s41596-018-0098-2","volume":"14","author":"L Heirendt","year":"2019","unstructured":"Heirendt, L. et al. Creation and analysis of biochemical constraint-based models using the COBRA Toolbox vol 3.0. Nat. Protocols 14, 639\u2013702. https:\/\/doi.org\/10.1038\/s41596-018-0098-2 (2019).","journal-title":"Nat. Protocols"},{"key":"55960_CR71","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1186\/1471-2105-11-489","volume":"11","author":"S Gudmundsson","year":"2010","unstructured":"Gudmundsson, S. & Thiele, I. Computationally efficient flux variability analysis. BMC Bioinform. 11, 489 (2010).","journal-title":"BMC Bioinform."},{"key":"55960_CR72","doi-asserted-by":"publisher","first-page":"107908","DOI":"10.1016\/j.celrep.2020.107908","volume":"32","author":"YW Wan","year":"2020","unstructured":"Wan, Y. W. et al. Meta-analysis of the alzheimer\u2019s disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 32, 107908. https:\/\/doi.org\/10.1016\/j.celrep.2020.107908 (2020).","journal-title":"Cell Rep."}],"updated-by":[{"DOI":"10.1038\/s41598-024-78228-2","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-55960-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-55960-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-55960-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T05:05:07Z","timestamp":1731387907000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-55960-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,13]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["55960"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-55960-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3306891\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,13]]},"assertion":[{"value":"29 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2024","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41598-024-78228-2","URL":"https:\/\/doi.org\/10.1038\/s41598-024-78228-2","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"G.K. and M.A. are co-inventors of several patent applications on the use of metabolomics in Alzheimer\u2019s disease and own equity and IP in Chymia LLC and IP in PsyProtix unrelated to this work. R.K.D. is an inventor of a series of patents on the use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix. S.T. has served on national and international advisory boards of Roche, Eisai, Grifols, and Biogen, and is a member of the independent data safety and monitoring board of the study ENVISION (Biogen). H.J.G. has received travel grants and speaker\u2019s honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care. R.K. is a scientific advisory board member, and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. D.M. is a consultant for, and has stock in, BiomeSense, Inc. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6095"}}