The exposome of brain aging across 34 countries

The physical and social exposome affects human aging, and brain clocks may track its effects. However, most studies neglect multidomain exposures (physical, social and political) across diverse settings globally and their associations with brain aging. In this study, we characterized the associations between 73 country-level physical and social exposomal factors and multimodal brain age in 18,701 participants from 34 countries (healthy individuals and those with Alzheimer's disease, frontotemporal lobar degeneration or mild cognitive impairment). Exposome effects were assessed using generalized additive models and meta-analytic frameworks. Aggregated exposome models explained up to 15.5-fold more variance than individual exposures (delta Akaike information criterion (ΔAIC): 2,034-3,127). Physical exposome was primarily associated with accelerated structural brain aging (limbic, subcortical and cerebellar regions), whereas social exposome was more strongly associated with functional brain aging (frontotemporal and limbic networks). Exposome burden accounted for 3.3-9.1-fold higher risk of accelerated aging, exceeding effects of clinical diagnoses. Findings were out-of-sample validated in cross-sectional and longitudinal designs, remained consistent across clinical subgroups and persisted after adjustment for demographics, age correction bias, cognition, scanner type and data quality. The exposome accelerates brain aging in health and disease, underscoring the need to address physical, social and political inequities.

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Publication Details

Journal
Nature Medicine
Published
2026-04-03
DOI
https://doi.org/10.1038/s41591-026-04302-z
Citations
1
Primary Topic
Health, Environment, Cognitive Aging
Type
article
Field-Weighted Citation Impact
16.76
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article

The exposome of brain aging across 34 countries

Simone Reppermund, Olivier Colliot, María Eugenia López, Ruben A Herzog et al.
1 citations
Nature Medicine
Health, Environment, Cognitive Aging
16.76
article

The exposome of brain aging across 34 countries

Simone Reppermund, Olivier Colliot, María Eugenia López, Ruben A Herzog, Alfred Kongnyu NJAMNSHI, Gaetano Di Caterina, Ramón Landín-Romero, Gabriela Novotni, Eman M. Khedr, Maria Eugenia Godoy, Renato Anghinah, Ewa Kublik, Marc Joliot, Vicente Medel, John Fredy Ochoa-Gómez, Pablo Barttfeld, Leon Aksman, Paula Margaretic, Sebastián Moguilner, Juan F. Cardona, Brenda Nadia Chino Vilca, Sol Fittipaldi, D. Aguirre Matallana, Jessica L. Hazelton, R. Whelan, Rahul Gaurav, Patricio Orio, Ricardo Bruña, Maira Okada de Oliveira, Sheri‐Michelle Koopowitz, Marcelo Adrián Maito, Juan Manuel Esquivias Farias, Raúl González-Gómez, Sarael Alcauter, Mehmet Ozansoy, Jinkook Lee, Fabrice Crivello, Faheem Arshad, Patrycja Dzianok, Temitope Farombi, May Bakr, C. Chen, Laz Ude Eze, Cecilia González Campo, Burcin Ikiz, Josephine Cruzat, Giovanni Abrahão Salum, Stéphanie Debette, M. Lourdes Bruno, Elissaios Karageorgiou, Athanasia Alexoudi, Jordi Huguet, Adolfo M. García, Mario A. Parra, Jhosmary Cuadros Castro, Salomón Salazar-Londoño, S. Goy López, Alberto Fernández, Florencia Portillo, Juan Pablo Morales Sepúlveda, Alfredis González Hernández, Ana Luisa Sosa Ortíz, MarÍa Isabel Behrens, Ann Toh, Javier Palma-Espinosa, CHUKWUANUGO OGBUAGU, Dante Sebastián Galván Rial, Jonathan Adrian Zegarra Valdivia, Tiago de Souza Azzi, Carlos Coronel-Oliveros, Elisa de Paula França Resende, Juan Helen Zhou, José Alberto Avila-Funes, Nilton Custodio, Alexandros Tzallas, Wei Wen, Damián Dellavale, Sophie Matis, Haisam Atta, Lütfü Hanoğlu, Gonzalo Forno Martinic, Stefanie Danielle Piña Escudero, Bahar Güntekin, Agustina Legaz, Javier Escudero, Indira Garcia-Cordero, Francesca R. Farina, Jasmin Bonilla Santos, Andreas Miltiadous, Lucia Amoruso, Andrea Slachevsky, Joaquin Migeot, Leonel Tadao Takada, Quentin d’Acremont, Cecilia Jarne, Sandra Milena Castelblanco-Toro, Catherina Dhooge, Saima Hilal, Görsev Yener, Tavia E. Evans
article en
1 citations

Abstract

The physical and social exposome affects human aging, and brain clocks may track its effects. However, most studies neglect multidomain exposures (physical, social and political) across diverse settings globally and their associations with brain aging. In this study, we characterized the associations between 73 country-level physical and social exposomal factors and multimodal brain age in 18,701 participants from 34 countries (healthy individuals and those with Alzheimer's disease, frontotemporal lobar degeneration or mild cognitive impairment). Exposome effects were assessed using generalized additive models and meta-analytic frameworks. Aggregated exposome models explained up to 15.5-fold more variance than individual exposures (delta Akaike information criterion (ΔAIC): 2,034-3,127). Physical exposome was primarily associated with accelerated structural brain aging (limbic, subcortical and cerebellar regions), whereas social exposome was more strongly associated with functional brain aging (frontotemporal and limbic networks). Exposome burden accounted for 3.3-9.1-fold higher risk of accelerated aging, exceeding effects of clinical diagnoses. Findings were out-of-sample validated in cross-sectional and longitudinal designs, remained consistent across clinical subgroups and persisted after adjustment for demographics, age correction bias, cognition, scanner type and data quality. The exposome accelerates brain aging in health and disease, underscoring the need to address physical, social and political inequities.

Nature Medicine
Universidad de Santiago de Chile (CL), Universidade Federal de Minas Gerais (BR), Ikerbasque (ES), University of Southern California (US), Universidad Complutense de Madrid (ES), Universidad Nacional Experimental del Táchira (VE), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), The University of Sydney (AU), Universidade Federal do Rio Grande do Sul (BR), Université de Yaoundé I (CM), Universidad del Desarrollo (CL), Climate Central (US), Universidad de Deusto (ES), National University of Quilmes (AR), Radboud University Nijmegen (NL), Université de Bordeaux (FR), Consejo Nacional de Investigaciones Científicas y Técnicas (AR), Inserm (FR), University of Cape Town (ZA), Pontificia Universidad Católica de Chile (CL), National University of Singapore (SG), Universidad Nacional de Córdoba (AR), Universidade de São Paulo (BR), University of California, San Francisco (US), University of Strathclyde (GB), Universidad de Guadalajara (MX), Dokuz Eylül University (TR), National and Kapodistrian University of Athens (GR), Aarhus University (DK), Trinity College Dublin (IE), Nnamdi Azikiwe University (NG), Adolfo Ibáñez University (CL), Pontificia Universidad Javeriana (CO), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), University College Hospital, Ibadan (NG), Radboud University Medical Center (NL), Bariloche Atomic Centre (AR), Istanbul Medipol University (TR), UNSW Sydney (AU), Universidad de Antioquia (CO), Sorbonne Université (FR), University of Chicago (US), University of San Andrés (AR), Institut des Maladies Neurodégénératives (FR), Instituto de Salud Pública de Chile (CL), Central Hospital of Yaoundé (CM), Centro Científico Tecnológico - San Juan (AR), Institute for Cross-Disciplinary Physics and Complex Systems (ES), Hospital de Clínicas de Porto Alegre (BR), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX), Hospital del Salvador (CL), Achucarro Basque Center for Neuroscience (ES), Child Mind Institute (US), Basque Center on Cognition, Brain and Language (ES), Bordeaux Population Health (FR), Faculdade de Ciências Médicas de Minas Gerais (BR), Pasqual Maragall Foundation (ES), South Eastern Europe Telecommunications Academy (GR), Neurological Institute of Athens (GR), Finis Terrae University (CL), AIDS Prevention Initiative in Nigeria (NG), Instituto de Neurología Cognitiva (AR), International Institute of Molecular and Cell Biology (PL), Universidad Católica de Cuyo (AR), Barcelonaβeta Brain Research Center (ES), Neuroimaging and Psychiatry (FR), Hospital Clínico de la Universidad de Chile (CL), Fundación Santa Fe de Bogotá (CO), Instituto de Neurociencia Biomédica (CL), Center for Innovation (US), Nnamdi Azikiwe University Teaching Hospital (NG), PHI University Psychiatric Clinic - Skopje (MK), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Instituto Nacional de Neurología y Neurocirugía (MX), Center for Climate and Resilience Research (CL), National University Health System (SG), Amsterdam University Medical Centers (NL), Universidad Cooperativa de Colombia (CO), Institut du Cerveau (FR), Hospital Universitario San Ignacio (CO), Global Brain Health Institute (US), Universidad de la Ciénega (MX), Institute of Neurobiology (BG), Evangelismos Hospital (GR), University of Chile (CL), National Institute of Mental Health and Neurosciences (IN), Federico Santa María Technical University (CL), Universidad Surcolombiana (CO), Ss. Cyril and Methodius University in Skopje (MK), University of Valparaíso (CL), American University in Cairo (EG), Sapienza University of Rome (IT), Universidad Nacional Autónoma de México (MX), Assiut University (EG), Universidad del Valle (CO), University of Edinburgh (GB)
Reduced inequalities
Openalex Percentile: Top 1%
Health, Environment, Cognitive Aging
16.76
DOIOpen Access PDFOpenAlex
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