Cortical thickness subtypes in cognitively unimpaired individuals: Differential network and transcriptomic vulnerability to cortical thinning

Luigi Lorenzini^{1

2}, Mario Tranfa^{1

3}, Leonard Pieperhoff^{1

4}, Federico Masserini^{1

5}, Mara Ten Kate^{1

6}, Lyduine E Collij^{1

4

7}, Giuseppe Pontillo^{1

3

8

9}, Emma S Luckett^{1

4

10

11}, Alle Meije Wink^{1

4}, Henk Jmm Mutsaerts^{1

4}, Tiago Gil Oliveira^{12

13}, Daniele Altomare¹⁴, Mercè Boada^{15

16}, Anouk den Braber^{6

17}, Cindy Birck¹⁸, Christopher Buckley¹⁹, Gill Farrar¹⁹, Wiesje van der Flier^{6

17

20}, Giovanni B Frisoni²¹, Rossella Gismondi²², Juan Domingo Gispert²³, Bernard J Hanseeuw^{24

25}, Frank Jessen²⁶, Marta Marquié^{15

16}, Anja Mett¹⁹, Craig Ritchie²⁷, Gemma Salvadó^{7

23}, Michael Schöll^{28

29

30}, Mahnaz Shekari^{23

31}, Andrew W Stephens²², Betty M Tijms^{6

17}, David Vállez García²³, Rik Vandenberghe³², Pieter Jelle Visser^{6

17

33}, Luca Roccatagliata^{34

35}, Neil P Oxtoby³⁶, Matteo Pardini^{2

37}, Frederik Barkhof^{1

38}

Affiliations

¹ Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Vrije Universiteit, Amsterdam, The Netherlands.
² Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.
³ Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy.
⁴ Amsterdam Neuroscience, Brain imaging, Amsterdam, the Netherlands.
⁵ Department of Biomedical and Clinical Sciences, Neuroscience Research Center, University of Milan, Milan, Italy.
⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam UMC, Amsterdam, The Netherlands.
⁷ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
⁸ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁹ Department of Anatomy and Neurosciences, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹⁰ Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
¹¹ Laboratory for Complex Genetics, KU Leuven, Leuven, Belgium.
¹² Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
¹³ ICVS/3B's-PT Government Associate Laboratory, University of Minho, Braga/Guimarães, Portugal.
¹⁴ 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.
¹⁵ Ace Alzheimer Center, Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain.
¹⁶ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
¹⁷ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
¹⁸ Alzheimer Europe, Alzheimer Europe, Bertrange, Luxembourg.
¹⁹ GE HealthCare, GE HealthCare, Amersham, UK.
²⁰ Department of Epidemiology & Biostatistics, Amsterdam Neuroscience, Amsterdam, Amsterdam, The Netherlands.
²¹ Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland.
²² Life Molecular Imaging, Life Molecular Imaging, Berlin, Germania.
²³ Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
²⁴ Department of Neurology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgio.
²⁵ Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
²⁶ Department of Psychiatry and Psychotherapy, University Hospital Cologne, Cologne, Germany.
²⁷ Scottish Brain Sciences, Scottish Brain Sciences, Edinburgh, Scotland.
²⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁹ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
³⁰ Dementia Research Centre, Institute of Neurology, University College London, London, UK.
³¹ Hospital del Mar Medical Research Institute (IMIM), PRBB Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
³² Leuven Brain Institute, KU Leuven, Leuven, Belgium.
³³ Department of Psychiatry, Maastricht University, Maastricht, the Netherlands.
³⁴ Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
³⁵ Department of Neuroradiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³⁶ UCL Hawkes Institute and Department of Computer Science, University College London, London, UK.
³⁷ Clinica Neurologica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³⁸ Institutes of Neurology and Healthcare Engineering, University College London, London, UK.

PMID: 41085135
PMCID: PMC12519513
DOI: 10.1002/alz.70762

Cortical thickness subtypes in cognitively unimpaired individuals: Differential network and transcriptomic vulnerability to cortical thinning

Luigi Lorenzini et al. Alzheimers Dement. 2025 Oct.

. 2025 Oct;21(10):e70762.

doi: 10.1002/alz.70762.

Authors

Affiliations

¹ Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Vrije Universiteit, Amsterdam, The Netherlands.
² Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.
³ Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy.
⁴ Amsterdam Neuroscience, Brain imaging, Amsterdam, the Netherlands.
⁵ Department of Biomedical and Clinical Sciences, Neuroscience Research Center, University of Milan, Milan, Italy.
⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam UMC, Amsterdam, The Netherlands.
⁷ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
⁸ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁹ Department of Anatomy and Neurosciences, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹⁰ Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
¹¹ Laboratory for Complex Genetics, KU Leuven, Leuven, Belgium.
¹² Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
¹³ ICVS/3B's-PT Government Associate Laboratory, University of Minho, Braga/Guimarães, Portugal.
¹⁴ 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.
¹⁵ Ace Alzheimer Center, Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain.
¹⁶ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
¹⁷ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
¹⁸ Alzheimer Europe, Alzheimer Europe, Bertrange, Luxembourg.
¹⁹ GE HealthCare, GE HealthCare, Amersham, UK.
²⁰ Department of Epidemiology & Biostatistics, Amsterdam Neuroscience, Amsterdam, Amsterdam, The Netherlands.
²¹ Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland.
²² Life Molecular Imaging, Life Molecular Imaging, Berlin, Germania.
²³ Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
²⁴ Department of Neurology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgio.
²⁵ Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
²⁶ Department of Psychiatry and Psychotherapy, University Hospital Cologne, Cologne, Germany.
²⁷ Scottish Brain Sciences, Scottish Brain Sciences, Edinburgh, Scotland.
²⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁹ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
³⁰ Dementia Research Centre, Institute of Neurology, University College London, London, UK.
³¹ Hospital del Mar Medical Research Institute (IMIM), PRBB Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
³² Leuven Brain Institute, KU Leuven, Leuven, Belgium.
³³ Department of Psychiatry, Maastricht University, Maastricht, the Netherlands.
³⁴ Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
³⁵ Department of Neuroradiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³⁶ UCL Hawkes Institute and Department of Computer Science, University College London, London, UK.
³⁷ Clinica Neurologica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³⁸ Institutes of Neurology and Healthcare Engineering, University College London, London, UK.

PMID: 41085135
PMCID: PMC12519513
DOI: 10.1002/alz.70762

Abstract

Introduction: The emergence, stability, and contributing factors of Alzheimer's disease (AD) gray matter subtypes remain unclear.

Methods: We analyzed data from 1323 individuals without a diagnosis of dementia (CDR < 1) with T1w-MRI and amyloid-PET, including 622 with longitudinal data (3.66 ± 1.78 years). Cortical thickness subtypes were identified using a non-negative matrix factorization (NMF) clustering algorithm. We examined clinical and demographic differences, subtype stability, and longitudinal thinning patterns using brain network models and imaging-transcriptomic analysis. Replication was performed with an alternative clustering approach and a validation cohort.

Results: Two stable subtypes emerged: limbic-predominant and hippocampal-sparing. Limbic-predominant participants were older, had higher amyloid burden, and faster memory decline, while hippocampal-sparing individuals showed greater attention and executive function decline. Distinct thinning patterns were linked to specific network properties and gene expression profiles.

Discussion: These MRI-based subtypes reflect underlying pathophysiological mechanisms and may aid in prognostication and clinical trial stratification.

Highlights: Two gray matter thickness subtypes can already be identified in preclinical stages, exhibiting distinct clinical characteristics and progression patterns. Individual subtype assignment remains stable over time. Longitudinal cortical thinning patterns follow distinct network- and transcriptomic-based mechanisms within each subtype.

Keywords: biological pathways; magnetic resonance imaging; polygenic risk; preclinical Alzheimer's.

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Conflict of interest statement

F.B. is supported by Engineering and Physical Sciences Research Council (EPSRC), EUJU (IMI), National Institute for Health and Care Research—Biomedical Research Center (NIHR‐BRC), General Eletronic (GE) HealthCare; he is a consultant for Combinostics, IXICO, and Roche; participates on advisory boards of Biogen, Prothena, and Merck; and is a co‐founder of Queen Square Analytics. L.E.C. has received research support and speakers fee from GE HealthCare Ltd. and Springer Healthcare (paid to institution). M.P. #NEXTGENERATIONEU (NGEU) and funded by the Italian Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) – A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). T.G.O. has been a consultant for Sonae, Guidepoint and Lilly, has received fees as a speaker from Eisai and conference fees covered from Roche. N.P.O. is a consultant for Queen Square Analytics Limited (UK) on unrelated topics. M.B. has consulted for Grifols, Araclon Biotech, Roche, Biogen, Lilly, Merck, Novo‐Nordisk; has served in the Advisory Boards from Grifols, Roche, Lilly, Araclon Biotech, Merck, Biogen, Novo‐Nordisk, Bioiberica, Eisai, Servier, Schwabe Pharma; received fees from lectures from Roche, Biogen, Grifols, Nutricia, Araclon Biotech, Novo‐Nordisk, Eisai, Terumo, Schwabe Pharma; and reports research funding from Life Molecular Imaging, Bioiberica, Grifols, Araclon Biotech, Lilly, Roche, Janssen, Alzehon, Cortyzime, Novo Nordisk, Schwabe Pharma. M.M. has consulted for F. Hoffmann‐La Roche Ltd. and has served in the Spanish Scientific Advisory Board for biomarkers of Araclon Biotech. G.S. has received speaker fees from Springer and Adium. L.L., M.T., L.P., F.M., M.K., G.P., E.S.L., A.M.W., H.J.M.M., D.A., A.B., C.B., C.B., G.F., W.F., G.B.F., R.G., J.D.G., B.J.H., F.J., A.M., C.R., M.S., M.S., A.W.S., B.M.T., D.V.G., R.V., P.J.V., and L.R. have nothing to disclose. Author disclosures are available in the Supporting Information

Figures

**FIGURE 1**
Schematic overview of methodology.

**FIGURE 2**
Thickness Subtypes, demographics, and clinical differences. (A) The regional NMF scores (H) for regions assigned to each identified gray matter thickness subtype. Regional assignment to subtypes was based on NMF probability. (B) Significant (p < 0.05) regional differences between the two subtypes. Differences are reported as standardized beta values of linear models predicting regional thickness values using subtype assignment. (C) Differences in age, *APOE* ε4 carriership, baseline, and longitudinal amyloid (model estimates). *APOE, apolipoprotein E;* NMF, non‐negative matrix factorization.

**FIGURE 3**
Cognitive performance and decline in thickness subtypes. The left column shows time‐by‐subtype estimates in the four assessed cognitive domains. p‐Values of the interactions are reported in black. Beta values report the association with cognitive performance within each subtype. The middle and right columns show the association of NMF probability with longitudinal (interaction with time) cognitive outcomes. Models used continuous NMF probability; median split was used to create groups for visualization purposes. NMF, non‐negative matrix factorization.

**FIGURE 4**
Longitudinal cortical thinning and driving mechanism within thickness subtypes. (A) The effect of time on regional gray matter thickness values within the two subtypes. (B) The results of the coordinated deformation models, reporting significance based on the two computed p‐values for each connectivity template, within each subtype. (C) The results of the imaging transcriptomic analysis. On the left, the genes that showed a significant correlation of their expression maps with longitudinal cortical thinning within each subtype. On the right, a visualization of the enriched pathways within the significant genes. FC, functional connectivity; MS, morphological similarity; SC, structural connectivity.

**FIGURE 5**
Replication. (A) The subtypes identified using the SuStaIn algorithm on the discovery cohort. Rows represent regions of interest and columns represent stages. A visualization of the brain of the observed subtypes and stages is reported. Panel B shows the results of the NMF algorithm on the replication cohort. NMF, non‐negative matrix factorization.

See this image and copyright information in PMC

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Cortical thickness subtypes in cognitively unimpaired individuals: Differential network and transcriptomic vulnerability to cortical thinning

Affiliations

Cortical thickness subtypes in cognitively unimpaired individuals: Differential network and transcriptomic vulnerability to cortical thinning

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

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Full Text Sources