The exposome of brain aging across 34 countries

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Legaz, Agustina and Moguilner, Sebastian and Barttfeld, Pablo and Cuadros Castro, Jhosmary and Galván Rial, Dante Sebastián and Migeot, Joaquin and Farina, Francesca R. and Gonzalez-Gomez, Raul and Salazar-Londoño, Salomón and de Souza Azzi, Tiago and Alcauter, Sarael and Amoruso, Lucia and Anghinah, Renato and Bakr, May and Behrens, María Isabel and Bruno, Martin A. and Cardona, Juan Felipe and Chen, Christopher and Colliot, Olivier and Custodio, Nilton and D’Acremont, Quentin and Debette, Stéphanie and Dzianok, Patrycja and Güntekin, Bahar and Huguet, Jordi and Jarne, Cecilia and Joliot, Marc and Karageorgiou, Elissaios and Khedr, Eman M. and Koopowitz, Sheri-Michelle and Kublik, Ewa and Lee, Jinkook and Aksman, Leon and Lopez, Susanna and Margaretic, Paula and Matallana, Diana and Matis, Sophie and Miltiadous, Andreas and Novotni, Gabriela and Orio, Patricio and Parra, Mario A. and Reppermund, Simone and de Paula França Resende, Elisa and Salum, Giovanni Abrahão and Slachevsky, Andrea and Ortiz, Ana Luisa Sosa and Takada, Leonel Tadao and Toh, An Qi and Tzallas, Alexandros and Wen, Wei and Whelan, Robert and Yener, Görsev and Zegarra Valdivia, Jonathan Adrián and Alexoudi, Athanasia and Arshad, Faheem and Atta, Haisam and Avila-Funes, Jose Alberto and Santos, Jasmin Bonilla and Bruña, Ricardo and Castelblanco-Toro, Sandra Milena and Chino Vilca, Brenda Nadia and Coronel-Oliveros, Carlos and Crivello, Fabrice and Cruzat, Josephine and Dellavale, Damián and Dhooge, Catherina and Di Caterina, Gaetano and Escudero, Javier and Esquivias Farias, Juan Manuel and Eze, Laz Ude and Evans, Tavia E. and Farombi, Temitope and Fernández, Alberto and Fittipaldi, Sol and Portillo, Florencia and Martinic, Gonzalo Forno and García, Adolfo M. and Garcia-Cordero, Indira and Gaurav, Rahul and Godoy, Maria Eugenia and Gonzalez Campo, Cecilia and González Hernández, Alfredis and Hanoğlu, Lütfü and Hazelton, Jessica L. and Herzog, Rubén and Ikiz, Burcin and Njamnshi, Alfred Kongnyu and Landin-Romero, Ramon and López, María Eugenia and Maito, Marcelo Adrián and Medel, Vicente and Sepúlveda, Juan Pablo Morales and Ochoa Gómez, John Fredy and Ogbuagu, Chukwuanugo and de Oliveira, Maira Okada and Ozansoy, Mehmet and Palma-Espinosa, Javier and Hilal, Saima and Zhou, Juan Helen and Escudero, Stefanie Danielle Piña and Pitman, Julie Kay and Prado, Pavel and Ramírez González, Diego and Reyes, Pablo and Santamaría García, Hernando and Schröder, Johannes and Sitt, Jacobo Diego and Soliman, Radwa Kamel and Soto-Añari, Marcio and Thanissery, Nithin and Ito, Lucas Toshio and Tsuchida, Ami and Tzourio, Christophe and Yırıkoğulları, Harun and Yokoyama, Jennifer S. and Aguillon, David and Miller, Bruce and Alladi, Suvarna and Jiang, Yang and Navarro, Arcadi and Babiloni, Claudio and Huepe Artigas, David and Piguet, Olivier and Sosa, Pedro Antonio Valdes and Mostert, Cyprian M. and Tahmasian, Masoud and Li, Peng and Hu, Kun and Genon, Sarah and Stein, Dan J. and Maestú, Fernando and Pievani, Michela and Salama, Mohamed and Brodaty, Henry and Sachdev, Perminder S. and Lawlor, Brian and Eyre, Harris A. and Miranda, J. Jaime and Baez, Sandra and Tagliazucchi, Enzo and Duran-Aniotz, Claudia and Hernandez, Hernan and Ibanez, Agustin (2026) The exposome of brain aging across 34 countries. Nature Medicine, 32 (5). pp. 1838-1851. ISSN 1546-170X (https://doi.org/10.1038/s41591-026-04302-z)

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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.

ORCID iDs

Legaz, Agustina, Moguilner, Sebastian, Barttfeld, Pablo, Cuadros Castro, Jhosmary, Galván Rial, Dante Sebastián, Migeot, Joaquin, Farina, Francesca R., Gonzalez-Gomez, Raul, Salazar-Londoño, Salomón, de Souza Azzi, Tiago, Alcauter, Sarael, Amoruso, Lucia, Anghinah, Renato, Bakr, May, Behrens, María Isabel, Bruno, Martin A., Cardona, Juan Felipe, Chen, Christopher, Colliot, Olivier, Custodio, Nilton, D’Acremont, Quentin, Debette, Stéphanie, Dzianok, Patrycja, Güntekin, Bahar, Huguet, Jordi, Jarne, Cecilia, Joliot, Marc, Karageorgiou, Elissaios, Khedr, Eman M., Koopowitz, Sheri-Michelle, Kublik, Ewa, Lee, Jinkook, Aksman, Leon, Lopez, Susanna, Margaretic, Paula, Matallana, Diana, Matis, Sophie, Miltiadous, Andreas, Novotni, Gabriela, Orio, Patricio, Parra, Mario A. ORCID logoORCID: https://orcid.org/0000-0002-2412-648X, Reppermund, Simone, de Paula França Resende, Elisa, Salum, Giovanni Abrahão, Slachevsky, Andrea, Ortiz, Ana Luisa Sosa, Takada, Leonel Tadao, Toh, An Qi, Tzallas, Alexandros, Wen, Wei, Whelan, Robert, Yener, Görsev, Zegarra Valdivia, Jonathan Adrián, Alexoudi, Athanasia, Arshad, Faheem, Atta, Haisam, Avila-Funes, Jose Alberto, Santos, Jasmin Bonilla, Bruña, Ricardo, Castelblanco-Toro, Sandra Milena, Chino Vilca, Brenda Nadia, Coronel-Oliveros, Carlos, Crivello, Fabrice, Cruzat, Josephine, Dellavale, Damián, Dhooge, Catherina, Di Caterina, Gaetano ORCID logoORCID: https://orcid.org/0000-0002-7256-0897, Escudero, Javier, Esquivias Farias, Juan Manuel, Eze, Laz Ude, Evans, Tavia E., Farombi, Temitope, Fernández, Alberto, Fittipaldi, Sol, Portillo, Florencia, Martinic, Gonzalo Forno, García, Adolfo M., Garcia-Cordero, Indira, Gaurav, Rahul, Godoy, Maria Eugenia, Gonzalez Campo, Cecilia, González Hernández, Alfredis, Hanoğlu, Lütfü, Hazelton, Jessica L., Herzog, Rubén, Ikiz, Burcin, Njamnshi, Alfred Kongnyu, Landin-Romero, Ramon, López, María Eugenia, Maito, Marcelo Adrián, Medel, Vicente, Sepúlveda, Juan Pablo Morales, Ochoa Gómez, John Fredy, Ogbuagu, Chukwuanugo, de Oliveira, Maira Okada, Ozansoy, Mehmet, Palma-Espinosa, Javier, Hilal, Saima, Zhou, Juan Helen, Escudero, Stefanie Danielle Piña, Pitman, Julie Kay, Prado, Pavel, Ramírez González, Diego, Reyes, Pablo, Santamaría García, Hernando, Schröder, Johannes, Sitt, Jacobo Diego, Soliman, Radwa Kamel, Soto-Añari, Marcio, Thanissery, Nithin, Ito, Lucas Toshio, Tsuchida, Ami, Tzourio, Christophe, Yırıkoğulları, Harun, Yokoyama, Jennifer S., Aguillon, David, Miller, Bruce, Alladi, Suvarna, Jiang, Yang, Navarro, Arcadi, Babiloni, Claudio, Huepe Artigas, David, Piguet, Olivier, Sosa, Pedro Antonio Valdes, Mostert, Cyprian M., Tahmasian, Masoud, Li, Peng, Hu, Kun, Genon, Sarah, Stein, Dan J., Maestú, Fernando, Pievani, Michela, Salama, Mohamed, Brodaty, Henry, Sachdev, Perminder S., Lawlor, Brian, Eyre, Harris A., Miranda, J. Jaime, Baez, Sandra, Tagliazucchi, Enzo, Duran-Aniotz, Claudia, Hernandez, Hernan and Ibanez, Agustin;
CORE (COnnecting REpositories)