{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:50:46Z","timestamp":1791874246282,"version":"4.3.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":80,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UK Research and Innovation (UKRI) Future Leaders Fellowship","award":["MR\/S03546X\/1"],"award-info":[{"award-number":["MR\/S03546X\/1"]}]},{"name":"Race Against Dementia"},{"DOI":"10.13039\/501100017506","name":"Alzheimer\u2019s Society","doi-asserted-by":"publisher","award":["AS-JF-18-008"],"award-info":[{"award-number":["AS-JF-18-008"]}],"id":[{"id":"10.13039\/501100017506","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["ARUKSRF-2016B"],"award-info":[{"award-number":["ARUKSRF-2016B"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCL Centre for Doctoral Training in Intelligent"},{"name":"Integrated Imaging in Healthcare","award":["EP\/S021930\/1"],"award-info":[{"award-number":["EP\/S021930\/1"]}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M02492X\/1"],"award-info":[{"award-number":["MR\/M02492X\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Changes to the relative abundance of amyloid-beta (A\u03b2) peptides are hallmarks of Alzheimer\u2019s disease. Induced pluripotent stem cell (iPSC)-derived neurons offer a physiological model of A\u03b2 production. We employed unbiased, data-driven analyses to investigate combinations of A\u03b2 peptides as Alzheimer\u2019s disease biomarkers and the relative contribution of peptides to Alzheimer\u2019s disease pathogenesis.<\/jats:p>\n                  <jats:p>We measured A\u03b237, A\u03b238, A\u03b240, A\u03b242 and A\u03b243 in 10 iPSC-neuronal cultures from PSEN1 mutation carriers. We combined these data with published cell model data and used linear weighted combinations to (i) distinguish Alzheimer\u2019s disease from controls, and (ii) predict age-at-onset for PSEN1 mutations. Data-driven approaches distinguished A\u03b242 and A\u03b243 from shorter peptides, providing unbiased evidence for a greater association of A\u03b242 and A\u03b243 to disease pathogenesis, compared with shorter peptides (A\u03b237, A\u03b238 and A\u03b240). Weighted linear combinations of A\u03b2 peptides outperform A\u03b242\/40 and provide insights into relative peptide contribution as biomarkers. A representative weighted composite value ratio (wCVR) derived from all data, balancing both disease classification and age-at-onset prediction, was (21\u22c5A\u03b237+10\u22c5A\u03b238+69\u22c5A\u03b240)\/ \u00a0(94\u22c5A\u03b242+6\u22c5A\u03b243). This work suggests a practical non-parametric harmonization approach to employing A\u03b2 ratios as biomarkers for Alzheimer\u2019s disease, from multiple sites and assays. Building on this foundation, we applied a new model using weighted composite value ratios, which outperform existing biomarkers across all tasks. This underscores the value of integrating multiple peptides and assigning optimized weightings. The study confirms the association of A\u03b242 and A\u03b243 with Alzheimer\u2019s disease pathogenesis in a data-driven manner. Peptide weights further provide mechanistic insights into the relative contribution of each peptide to disease, such as a greater contribution of A\u03b237 compared to A\u03b238. The algorithm used herein can be further refined to improve biomarkers for Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag105","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T12:45:21Z","timestamp":1774010721000},"source":"Crossref","is-referenced-by-count":2,"title":["Unbiased data-driven analysis of five amyloid-beta peptides for biomarker investigations in familial Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"8","author":[{"given":"Isaac","family":"Llorente-Saguer","sequence":"first","affiliation":[{"name":"Department of Medical Physics and Biomedical Engineering and UCL Hawkes Institute, University College London , London WC1V 6LJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Gabriele","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3BG 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Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]},{"name":"Adelaide Medical School, The University of Adelaide , Adelaide, SA 5000 ,","place":["Australia"]},{"name":"Department of Neurology, Royal Adelaide Hospital and Queen Elizabeth Hospital , Adelaide, South Australia 5005 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Ch\u00e1vez-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"VIB-KU Leuven Center for Brain & Disease Research , Leuven 3001 ,","place":["Belgium"]},{"name":"Department of Neurosciences, Leuven Research Institute for Neuroscience and Disease (LIND) , KU Leuven, Leuven 3001 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-5775","authenticated-orcid":false,"given":"Rohan","family":"de Silva","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, Reta Lila Weston Institute, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick C","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]},{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]},{"name":"UK Dementia Research Institute at UCL , London WC1E 6BT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3062-7050","authenticated-orcid":false,"given":"Selina","family":"Wray","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3BG 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