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Publications

Journal Article Ahead of print

PubMed: 42265349 DOI: 10.1038/s43856-026-01707-2

Decreased amyloid-related structure-function coupling in preclinical Alzheimer's disease.

Commun Med (Lond)

Authors: Prithvi Arunachalam, Leonard Pieperhoff, Luigi Lorenzini, Mario Tranfa, Federico Masserini, Francesca Treves, Giuseppe Pontillo, Maria G Preti, Tommy A A Broeders, Menno M Schoonheim, Linda Douw, Craig Ritchie, Mercè Boada, Marta Marquié, Pieter Jelle Visser, Raffaele Cacciaglia, Juan Domingo Gispert, Gemma Salvadó, Emma S Luckett, Lyduine E Collij, James H Cole, Frederik Barkhof, Alle Meije Wink

Affiliations

  • Department of Radiology and Nuclear Medicine, UMC Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Amsterdam Neuroscience, Brain Imaging, Amsterdam, the Netherlands.
  • Department of Radiology and Nuclear Medicine, UMC Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Amsterdam Neuroscience, Brain Imaging, Amsterdam, the Netherlands.
  • Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.
  • Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
  • Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy.
  • Department of Biomedical and Clinical Sciences, Neuroscience Research Center, University of Milan, Milan, Italy.
  • Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
  • UCL Queen Square Institute of Neurology, University College London, London, UK.
  • Neuro-X Institute, Ecole Polytechnique Fédérale De Lausanne (EPFL), Geneva, Switzerland.
  • Department of Radiology and Medical Informatics, University of Geneva (UNIGE), Geneva, Switzerland.
  • MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Scottish Brain Sciences, Edinburgh, Scotland.
  • Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.
  • Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
  • Alzheimer Center Amsterdam, Department of Neurology, Amsterdam UMC, Amsterdam, the Netherlands.
  • Department of Psychiatry, Maastricht University, Maastricht, the Netherlands.
  • Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
  • Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
  • Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain.
  • Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
  • Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium.
  • Laboratory for Complex Genetics, KU Leuven, Leuven, Belgium.
  • Hawkes Institute, Department of Computer Science, UCL, London, UK.
  • Dementia Research Centre, Queen Square Institute of Neurology, UCL, London, UK.

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.

MeSH

Genes, Alzheimer Disease, Brain, Amyloid, Cognition