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.
Plain language summary
Alzheimer’s disease (AD) affects how different parts of the brain communicate and results in changes in people’s behaviour and ability to remember and think. In its early stages, before symptoms appear, changes in brain connections may already be happening. In this study, we examined how a key protein known to be involved in AD called amyloid-β affects the relationship between brain structure and brain activity, known as structure–function coupling, in older adults without dementia. We analysed brain scans from 460 participants and used a measure called the structural-decoupling index to assess this relationship. We found that higher amyloid-β levels were linked to weaker alignment between brain structure and function, especially in brain regions involved in sight. Our findings suggest that early changes in structure–function coupling could be used to monitor disease progression and support future prevention strategies.
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Acknowledgements
This work used data from AMYPAD—PNHS (Amyloid Imaging to Prevent Alzheimer’s Disease–prognostic and natural history study) and EPAD LCS (European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study). The authors would like to express their most sincere gratitude to the AMYPAD and EPAD participants, without whom this research would not have been possible. As such, investigators within the AMYPAD PNHS and AMYPAD Consortium contributed to the design and implementation of AMYPAD and/or provided data but did not participate in the analysis or writing of this report. A complete list of AMYPAD investigators and consortium members can be found at https://doi.org/10.5281/zenodo.7962737 and in Supplementary Materials. We also gratefully acknowledge Sumeet Dash for his insightful discussions and valuable conceptual input that helped shape aspects of this work.
Funding
This work is part of the project “Early Multi-layer Brain network model biomarkers of ALzheiMer’s disease”, Alzheimer Nederland Biomedical Research grant no. WE.03-2023-14. The study was supported by the Alzheimer’s Disease Data Initiative (ADDI). AMYPAD received funding from the Innovative Medicines Initiative (IMI) 2 Joint Undertaking under grant agreement No 115952. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA. EPAD received funding from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EPAD grant agreement number. 115736 and an Alzheimer’s Association Grant (SG-21-818099-EPAD). This paper reflects the views of the authors, and neither IMI nor the European Union and EFPIA is liable for any use that may be made of the information contained herein. F.B. and A.M. have received support for data curation and storage from Alzheimer’s Disease Data Initiative (ADDI; paid to institution). LL receives funding from the MSCA postdoctoral fellowship (#101204296). M.B. received funding from CIBERNED (Instituto de Salud Carlos III (ISCIII); EU/EFPIA Innovative Medicines Initiative Joint Undertaking, ADAPTED Grant No. 115975; EXIT project, EU Euronanomed3 Programme JCT2017 Grant No. AC17/00100; MOPEAD, Innovative Medicine Initiative, Grant. No. 115985; PreDADQoL, ERA-NET (call 2015). Grant no. AC15/00082; TARTAGLIA (Red federada para accelerar la aplicación de la inteligencia artificial en el sistema sanitario español); PREADAPT project, Joint Programme for Neurodegenerative Diseases (JPND) Grant No. AC19/00097; GECONEU Grant No. 2023-1-ELO1-KAZZ0-HED-000032173 co-founded by the European Union; Grants PI13/02434, PI16/01861, BA19/00020, and PI19/01301 from the Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by Instituto de Salud Carlos III (ISCIII)- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER – “Una manera de Hacer Europa”); Fundació “La Caixa” and Grífols (GR@ACE project); and Proyectos de Investigación de Medicina Personalizada (ISCIII), PMP-DEGESCO, Grant N° PMP22/00022. M.M. has received funding support from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement no. 796706 and the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—Una manera de hacer Europa) grant PI19/00335.
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F.B. is supported by Engineering and Physical Sciences Research Council (EPSRC), EUJU (IMI), National Institute for Health and Care Research—Biomedical Research Centre (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). C.R. is a CEO, founder and majority shareholder of Scottish Brain Sciences, Edinburgh, UK, and has received funding paid to his institution for projects, consultancy, or investigator fees from Actinogen, Biogen, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd, Janssen-Cilag GmbH, Kynexis, Linus, Merck, Novartis, Roche Diagnostics International Ltd, TauRx, and Thereni. 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 or advisory fees from Springer, GE Healthcare, Biogen, Esteve, Adium and Johnson&Johnson. All other authors declare no competing interests.
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Arunachalam, P., Pieperhoff, L., Lorenzini, L. et al. Decreased amyloid-related structure–function coupling in preclinical Alzheimer’s disease. Commun Med (2026). https://doi.org/10.1038/s43856-026-01707-2
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DOI: https://doi.org/10.1038/s43856-026-01707-2
