Decreased amyloid-related structure–function coupling in preclinical Alzheimer’s disease

BACKGROUND: Structural pathways of the brain facilitate functional communication, and their disruption in preclinical Alzheimer's disease may reflect network vulnerability and compensatory brain maintenance. However, it remains unclear how early amyloid-β affects structure-function alignment, whether effects are explained by functional network organisation, how they relate to cognition, and which biological processes contribute to their development. METHODS: We included 460 older adults without dementia from AMYPAD-PNHS with functional MRI, diffusion MRI, and amyloid-β PET. Structure-function coupling was quantified using the structural-decoupling index (SDI) at global, sub-network, and regional scales. Linear models investigated the effect of amyloid-β burden on SDI. Mediation analyses evaluated whether functional graph topology explained amyloid-associated SDI effects and whether SDI mediated the relationship between amyloid-β burden and cognition. Regional gene expression data were integrated to assess transcriptomic determinants of amyloid-related structure-function coupling. RESULTS: Amyloid-positive individuals exhibit higher global SDI, driven by visual cortices. Mediation analyses demonstrate that amyloid-related SDI alterations are explained by reductions in local clustering, indicating less segregated processing. Despite higher SDI in amyloid-positive individuals, elevated SDI in visual regions mitigates the negative effect of amyloid-β burden on cognition. Amyloid-related SDI changes correlate with genes associated with amyloid-β metabolism, microglial activation, and synaptic remodelling. CONCLUSIONS: Early amyloid-β pathology is associated with decoupling of brain structure and function, primarily in visual cortices, mediated by network reconfiguration and shaped by regional molecular architecture. These findings suggest that lower structure-function coupling may represent a compensatory mechanism in preclinical Alzheimer's disease and highlight SDI as a biomarker for stratification and monitoring in prevention trials.

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Publication Details

Journal
Communications Medicine
Published
2026-06-09
DOI
https://doi.org/10.1038/s43856-026-01707-2
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

Decreased amyloid-related structure–function coupling in preclinical Alzheimer’s disease

Emma S. Luckett, Lyduine E. Collij, James H. Cole, Rossella Gismondi et al.
Communications Medicine
Alzheimer's disease research and treatments
article

Decreased amyloid-related structure–function coupling in preclinical Alzheimer’s disease

Emma S. Luckett, Lyduine E. Collij, James H. Cole, Rossella Gismondi, Isadora Lopes Alves, Luigi Lorenzini, Adrian Ivanoiu, Mario Tranfa, Laure Saint‐Aubert, Maria Giulia Preti, Raffaele Cacciaglia, Prithvi Arunachalam, Oriol Grau Rivera, Daniele Altomare, Gill Farrar, Pablo Martínez Lage, Federico Masserini, Linda Douw, Christopher Buckely, Peter Connely, Leonard Pieperhoff, Francesca Treves, Alle Meije Wink, Juan Domingo Gispert, Julien Dumurgier, Ingmar Skoog, José Luis Molinuevo, Lisa Ford, Giuseppe Pontillo, Gemma Salvadó, Craig Ritchie, Mark Schmidt, Miia Kivipelto, Anouk Den Braber, Bart N. M. van Berckel, Florence Pasquier, Philip Scheltens, Pieter Jelle Visser, Alexander Drzezga, Menno M. Schoonheim, Giovanni B. Frisoni, Katherine R. Gray, Claire Boutoleau-Bretonniere, Robin Wolz, Rik Vandenberghe, Michael Schöll, Annebet Leeuwis, Mercè Boada, Frederik Barkhof, Pierre Payoux, Bruno Dubois, Silke Kern, Bruno Vellas, Pierre-Jean Ousset, Marta Marquié, Bernard J. Hanseeuw, Frank Jessen, Audrey Gabelle, Andrew Stephens, Tommy A. A. Broeders
article en

Abstract

BACKGROUND: Structural pathways of the brain facilitate functional communication, and their disruption in preclinical Alzheimer's disease may reflect network vulnerability and compensatory brain maintenance. However, it remains unclear how early amyloid-β affects structure-function alignment, whether effects are explained by functional network organisation, how they relate to cognition, and which biological processes contribute to their development. METHODS: We included 460 older adults without dementia from AMYPAD-PNHS with functional MRI, diffusion MRI, and amyloid-β PET. Structure-function coupling was quantified using the structural-decoupling index (SDI) at global, sub-network, and regional scales. Linear models investigated the effect of amyloid-β burden on SDI. Mediation analyses evaluated whether functional graph topology explained amyloid-associated SDI effects and whether SDI mediated the relationship between amyloid-β burden and cognition. Regional gene expression data were integrated to assess transcriptomic determinants of amyloid-related structure-function coupling. RESULTS: Amyloid-positive individuals exhibit higher global SDI, driven by visual cortices. Mediation analyses demonstrate that amyloid-related SDI alterations are explained by reductions in local clustering, indicating less segregated processing. Despite higher SDI in amyloid-positive individuals, elevated SDI in visual regions mitigates the negative effect of amyloid-β burden on cognition. Amyloid-related SDI changes correlate with genes associated with amyloid-β metabolism, microglial activation, and synaptic remodelling. CONCLUSIONS: Early amyloid-β pathology is associated with decoupling of brain structure and function, primarily in visual cortices, mediated by network reconfiguration and shaped by regional molecular architecture. These findings suggest that lower structure-function coupling may represent a compensatory mechanism in preclinical Alzheimer's disease and highlight SDI as a biomarker for stratification and monitoring in prevention trials.

Communications Medicine
University of Geneva (CH), Scottish Agricultural Science Agency (GB), Lund University (SE), University of Milan (IT), University of Pavia (IT), Hawkeye Community College (US), Instituto de Salud Carlos III (ES), Universitat Internacional de Catalunya (ES), Maastricht University (NL), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Pasqual Maragall Foundation (ES), Amsterdam Neuroscience (NL), Federico II University Hospital (IT), UK Dementia Research Institute (GB), Barcelonaβeta Brain Research Center (ES), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (ES), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), Hospital del Mar Research Institute (ES), University College London (GB), École Polytechnique Fédérale de Lausanne (CH), University of Genoa (IT), Vrije Universiteit Amsterdam (NL), KU Leuven (BE)
Alzheimer's Association, European Federation of Pharmaceutical Industries and Associations, Alzheimer Nederland
Openalex Percentile: Top 7%
Alzheimer's disease research and treatments
DOIOpen Access PDFOpenAlex
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