{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:43:37Z","timestamp":1791297817446,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T00:00:00Z","timestamp":1714089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basque Government","award":["KK-2022\/00001"],"award-info":[{"award-number":["KK-2022\/00001"]}]},{"name":"Basque Government","award":["CEX2020-001038-M"],"award-info":[{"award-number":["CEX2020-001038-M"]}]},{"name":"MICIU\/AEI\/10.13039\/501100011033","award":["KK-2022\/00001"],"award-info":[{"award-number":["KK-2022\/00001"]}]},{"name":"MICIU\/AEI\/10.13039\/501100011033","award":["CEX2020-001038-M"],"award-info":[{"award-number":["CEX2020-001038-M"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease is a progressive neurodegenerative disorder, the early detection of which is crucial for timely intervention and enrollment in clinical trials. However, the preclinical diagnosis of Alzheimer\u2019s encounters difficulties with gold-standard methods. The current definitive diagnosis of Alzheimer\u2019s still relies on expensive instrumentation and post-mortem histological examinations. Here, we explore label-free Raman spectroscopy with machine learning as an alternative to preclinical Alzheimer\u2019s diagnosis. A special feature of this study is the inclusion of patient samples from different cohorts, sampled and measured in different years. To develop reliable classification models, partial least squares discriminant analysis in combination with variable selection methods identified discriminative molecules, including nucleic acids, amino acids, proteins, and carbohydrates such as taurine\/hypotaurine and guanine, when applied to Raman spectra taken from dried samples of cerebrospinal fluid. The robustness of the model is remarkable, as the discriminative molecules could be identified in different cohorts and years. A unified model notably classifies preclinical Alzheimer\u2019s, which is particularly surprising because of Raman spectroscopy\u2019s high sensitivity regarding different measurement conditions. The presented results demonstrate the capability of Raman spectroscopy to detect preclinical Alzheimer\u2019s disease for the first time and offer invaluable opportunities for future clinical applications and diagnostic methods.<\/jats:p>","DOI":"10.3390\/ijms25094737","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T08:18:27Z","timestamp":1714119507000},"page":"4737","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Unlocking Preclinical Alzheimer\u2019s: A Multi-Year Label-Free In Vitro Raman Spectroscopy Study Empowered by Chemometrics"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7581-1113","authenticated-orcid":false,"given":"Eneko","family":"Lopez","sequence":"first","affiliation":[{"name":"CIC nanoGUNE BRTA, 20018 San Sebasi\u00e1n, Spain"},{"name":"Department of Physics, University of the Basque Country (UPV\/EHU), 20018 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaione","family":"Etxebarria-Elezgarai","sequence":"additional","affiliation":[{"name":"CIC nanoGUNE BRTA, 20018 San Sebasi\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3480-6056","authenticated-orcid":false,"given":"Maite","family":"Garc\u00eda-Sebasti\u00e1n","sequence":"additional","affiliation":[{"name":"Center for Research and Advanced Therapies, CITA-Alzh\u00e9imer Foundation, 20009 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9709-5314","authenticated-orcid":false,"given":"Miren","family":"Altuna","sequence":"additional","affiliation":[{"name":"Center for Research and Advanced Therapies, CITA-Alzh\u00e9imer Foundation, 20009 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirian","family":"Ecay-Torres","sequence":"additional","affiliation":[{"name":"Center for Research and Advanced Therapies, CITA-Alzh\u00e9imer Foundation, 20009 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainara","family":"Estanga","sequence":"additional","affiliation":[{"name":"Center for Research and Advanced Therapies, CITA-Alzh\u00e9imer Foundation, 20009 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel","family":"Tainta","sequence":"additional","affiliation":[{"name":"Center for Research and Advanced Therapies, CITA-Alzh\u00e9imer Foundation, 20009 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Center for Research and Advanced Therapies, CITA-Alzh\u00e9imer Foundation, 20009 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Mart\u00ednez-Lage","sequence":"additional","affiliation":[{"name":"Center for Research and Advanced Therapies, CITA-Alzh\u00e9imer Foundation, 20009 San Sebasti\u00e1n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1319-1312","authenticated-orcid":false,"given":"Jose Manuel","family":"Amigo","sequence":"additional","affiliation":[{"name":"IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain"},{"name":"Department of Analytical Chemistry, University of the Basque Country, 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5849-4953","authenticated-orcid":false,"given":"Andreas","family":"Seifert","sequence":"additional","affiliation":[{"name":"CIC nanoGUNE BRTA, 20018 San Sebasi\u00e1n, Spain"},{"name":"IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1590\/1516-4446-2019-0735","article-title":"Early diagnosis and treatment of Alzheimer\u2019s disease: New definitions and challenges","volume":"42","author":"Pais","year":"2020","journal-title":"Braz J. 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