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