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Dementia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>The emergence, stability, and contributing factors of Alzheimer's disease (AD) gray matter subtypes remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We analyzed data from 1323 individuals without a diagnosis of dementia (CDR\u00a0&lt;\u00a01) with T1w\u2010MRI and amyloid\u2010PET, including 622 with longitudinal data (3.66\u00a0\u00b1\u00a01.78 years). Cortical thickness subtypes were identified using a non\u2010negative matrix factorization (NMF) clustering algorithm. We examined clinical and demographic differences, subtype stability, and longitudinal thinning patterns using brain network models and imaging\u2010transcriptomic analysis. Replication was performed with an alternative clustering approach and a validation cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Two stable subtypes emerged: limbic\u2010predominant and hippocampal\u2010sparing. Limbic\u2010predominant participants were older, had higher amyloid burden, and faster memory decline, while hippocampal\u2010sparing individuals showed greater attention and executive function decline. Distinct thinning patterns were linked to specific network properties and gene expression profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These MRI\u2010based subtypes reflect underlying pathophysiological mechanisms and may aid in prognostication and clinical trial stratification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Two gray matter thickness subtypes can already be identified in preclinical stages, exhibiting distinct clinical characteristics and progression patterns.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Individual subtype assignment remains stable over time.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Longitudinal cortical thinning patterns follow distinct network\u2010 and transcriptomic\u2010based mechanisms within each subtype.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70762","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T13:20:10Z","timestamp":1760448010000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cortical thickness subtypes in cognitively unimpaired individuals: Differential network and transcriptomic vulnerability to cortical thinning"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9756-881X","authenticated-orcid":false,"given":"Luigi","family":"Lorenzini","sequence":"first","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI) University of Genoa Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Tranfa","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Pieperhoff","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience Brain imaging Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Masserini","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Department of Biomedical and Clinical Sciences Neuroscience Research Center University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"ten Kate","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Alzheimer Center Amsterdam Department of Neurology Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyduine E.","family":"Collij","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience Brain imaging Amsterdam the Netherlands"},{"name":"Clinical Memory Research Unit Department of Clinical Sciences Malm\u00f6, Faculty of Medicine Lund University Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pontillo","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"},{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation UCL Queen Square Institute of Neurology University College London  London UK"},{"name":"Department of Anatomy and Neurosciences MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma S.","family":"Luckett","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience Brain imaging Amsterdam the Netherlands"},{"name":"Laboratory for Cognitive Neurology KU Leuven Leuven Belgium"},{"name":"Laboratory for Complex Genetics KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alle Meije","family":"Wink","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience Brain imaging Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk JMM","family":"Mutsaerts","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience Brain imaging Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago Gil","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS) School of Medicine University of Minho  Braga Portugal"},{"name":"ICVS\/3B's\u2013PT Government Associate Laboratory University of Minho Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Altomare","sequence":"additional","affiliation":[{"name":"Competence Centre on Ageing (CCA); Department of Business Economics Health and Social Care (DEASS); University of Applied Sciences and Arts of Southern Switzerland (SUPSI) Manno Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Boada","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona\u2013Universitat Internacional de Catalunya Barcelona Spain"},{"name":"Networking Research Center on Neurodegenerative Diseases (CIBERNED) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouk","family":"den Braber","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam Department of Neurology Amsterdam UMC  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience Neurodegeneration Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Birck","sequence":"additional","affiliation":[{"name":"Alzheimer Europe Alzheimer Europe 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Geriatrics Geneva University Hospitals Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Gismondi","sequence":"additional","affiliation":[{"name":"Life Molecular Imaging Life Molecular Imaging Berlin Germania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Domingo","family":"Gispert","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center Pasqual Maragall Foundation  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard J.","family":"Hanseeuw","sequence":"additional","affiliation":[{"name":"Department of Neurology Cliniques Universitaires Saint\u2010Luc  Bruxelles Belgio"},{"name":"Institute of Neuroscience Universit\u00e9 catholique de Louvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Jessen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy University Hospital Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Marqui\u00e9","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona\u2013Universitat Internacional de Catalunya Barcelona Spain"},{"name":"Networking Research Center on Neurodegenerative Diseases (CIBERNED) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Mett","sequence":"additional","affiliation":[{"name":"GE HealthCare GE HealthCare Amersham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Ritchie","sequence":"additional","affiliation":[{"name":"Scottish Brain Sciences Scottish Brain Sciences Edinburgh Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Salvad\u00f3","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit Department of Clinical Sciences Malm\u00f6, Faculty of Medicine Lund University Lund Sweden"},{"name":"Barcelona\u03b2eta Brain Research Center Pasqual Maragall Foundation  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sch\u00f6ll","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy, University of Gothenburg  Gothenburg Sweden"},{"name":"Wallenberg Centre for Molecular and Translational Medicine University of Gothenburg  Gothenburg Sweden"},{"name":"Dementia Research Centre, Institute of Neurology University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahnaz","family":"Shekari","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center Pasqual Maragall Foundation  Barcelona Spain"},{"name":"Hospital del Mar Medical Research Institute (IMIM) PRBB Parc de Recerca Biom\u00e8dica de Barcelona Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew W.","family":"Stephens","sequence":"additional","affiliation":[{"name":"Life Molecular Imaging Life Molecular Imaging Berlin Germania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty M.","family":"Tijms","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam Department of Neurology Amsterdam UMC  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience Neurodegeneration Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"V\u00e1llez Garc\u00eda","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center Pasqual Maragall Foundation  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Vandenberghe","sequence":"additional","affiliation":[{"name":"Leuven Brain Institute KU Leuven Leuven 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