The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study

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  • dc.contributor.author Cumplido-Mayoral, Irene
  • dc.contributor.author Brugulat Serrat, Anna, 1986-
  • dc.contributor.author Sánchez Benavides, Gonzalo
  • dc.contributor.author González Escalante, Armand
  • dc.contributor.author Anastasi, Federica
  • dc.contributor.author Milà Alomà, Marta
  • dc.contributor.author López Martos, David
  • dc.contributor.author Akinci, Muge
  • dc.contributor.author Falcón, Carles
  • dc.contributor.author Shekari, Mahnaz
  • dc.contributor.author Cacciaglia, Raffaele
  • dc.contributor.author Arenaza Urquijo, Eider M.
  • dc.contributor.author Minguillón, Carolina
  • dc.contributor.author Fauria, Karine
  • dc.contributor.author Molinuevo, José Luis
  • dc.contributor.author Suárez-Calvet, Marc
  • dc.contributor.author Grau-Rivera, Oriol
  • dc.contributor.author Vilaplana, Verónica
  • dc.contributor.author Gispert López, Juan Domingo
  • dc.contributor.author ALFA Study
  • dc.date.accessioned 2024-07-08T13:05:23Z
  • dc.date.available 2024-07-08T13:05:23Z
  • dc.date.issued 2024
  • dc.description.abstract Background: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain. Methods: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid β-amyloid (Aβ)42 and Aβ40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaβeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aβ-negative and Aβ-positive individuals. Findings: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aβ-positive and 194 as Aβ-negative. In Aβ-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22-16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25-29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aβ-negative individuals (3·52% [0·072-4·17]) on PACC, although path coefficients were not significantly different from those in the Aβ-positive group. Interpretation: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aβ-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline. Funding: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government. Translation: For the Spanish translation of the abstract see Supplementary Materials section.
  • dc.description.sponsorship This publication is part of the ALFA study. We thank the ALFA project participants and relatives, without whom this research would not have been possible. We thank Kaj Blennow and Henrik Zetterberg for performing the measurements of cerebrospinal fluid Aβ42:Aβ40 ratio. We thank Roche Diagnostics International for providing the kits to measure cerebrospinal fluid biomarkers. The Roche NeuroToolKit is a panel of exploratory prototype assays designed to evaluate biomarkers associated with key pathological events characteristic of Alzheimer's disease and other neurological disorders, used for research purposes only and not approved for clinical use. COBAS and ELECSYS are trademarks of Roche. All other product names and trademarks are the property of their respective owners. The ALFA+ study receives funding from La Caixa Foundation (100010434; LCF/PR/GN17/50300004) and the Alzheimer's Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa 17 519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government (2021 SGR 009132017-SGR-892). MS-C receives funding from the European Research Council under the EU Horizon 2020 research and innovation programme (948677; project PI19/00155), funded by Instituto de Salud Carlos III and co-funded by the EU, and from a fellowship from La Caixa Foundation (100010434) and from the EU Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (847648; LCF/BQ/PR21/11840004). DL-M is supported by Instituto de Salud Carlos III (PI19/00117; co-funded by European Regional Development Fund, European Social Fund A Way to Make Europe, and Investing in your Future). EMA-U is supported by the Spanish Ministry of Science and Innovation State Research Agency (RYC2018-026053-I), co-funded by the European Social Fund and the Spanish Ministry of Science and Innovation (PID2019-111514RA-I00). VV has been supported by the Spanish Research Agency (PID2020-116907RB-I00 of the call MCIN/AEI/10.13039/501100011033). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). JDG has also received research support from the EU and European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative Joint Undertaking AMYPAD (115952), European Institute of Innovation and Technology Digital (2021), and from Ministerio de Ciencia y Universidades (RTI2018-102261). GS-B receives funding from the Ministerio de Ciencia e Innovacion, Spanish Research Agency (PID2020-119556RA-I00). OG-R receives funding from the Alzheimer's Association Research Fellowship (2019-AARF-644568), from Instituto de Salud Carlos III (PI19/00117), and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva programme IJC2020-043417-I).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Cumplido-Mayoral I, Brugulat-Serrat A, Sánchez-Benavides G, González-Escalante A, Anastasi F, Milà-Alomà M, et al. The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study. Lancet Healthy Longev. 2024 Apr;5(4):e276-e286. DOI: 10.1016/S2666-7568(24)00025-4
  • dc.identifier.doi http://dx.doi.org/10.1016/S2666-7568(24)00025-4
  • dc.identifier.issn 2666-7568
  • dc.identifier.uri http://hdl.handle.net/10230/60698
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Lancet Healthy Longev. 2024 Apr;5(4):e276-e286
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/847648
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-111514RA-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-102261
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119556RA-I00
  • dc.rights © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.other Deteriorament cognitiu lleu
  • dc.subject.other Demència
  • dc.title The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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