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

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 ß-amyloid (Aß)42 and Aß40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaßeta 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 Aß-negative and Aß-positive individuals. Findings: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aß-positive and 194 as Aß-negative. In Aß-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22–16·66]) the association between modif
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), cofunded 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 (PID2020119556RA-I00). OG-R receives funding from the Alzheimer’s Association Research Fellowship (2019-AARF-644568), from Instituto de Salud Carlos III (P
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Article signat per 19 autors/autores: Irene Cumplido-Mayoral, Anna Brugulat-Serrat, Gonzalo Sánchez-Benavides, Armand González-Escalante, Federica Anastasi, Marta Milà-Alomà, David López-Martos, Muge Akinci, Carles Falcón, Mahnaz Shekari, Raffaele Cacciaglia, Eider M Arenaza-Urquijo, Carolina Minguillón, Karine Fauria, José Luis Molinuevo, Marc Suárez-Calvet, Oriol Grau-Rivera, Verónica Vilaplana, Juan Domingo Gispert, on behalf of the ALFA study*. * Membres del grup "ALFA study": Annabella Beteta, Alba Cañas, Marta del Campo, Carme Deulofeu, Ruth Dominguez, Maria Emilio, Ana Fernández-Arcos, Sherezade Fuentes, Patricia Genius, Laura Hernández, Jordi Huguet, Wiesje Pelkmans, Albina Polo, Sandra Pradas, Blanca Rodríguez-Fernández, Anna Soteras, Laura Stankeviciute, Marc Vilanova, Natalia Vilor-Tejedor.
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