Nat Med. 2026 Apr 3. doi: 10.1038/s41591-026-04302-z. Online ahead of print.
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.
PMID:41933172 | DOI:10.1038/s41591-026-04302-z
Authors
Sebastian Moguilner, PhD
Neuroscientist
Joaquín Migeot, MSc, PhD
Neuroscientist
Francesca Farina, PhD
Neuroscientist
Elissaios Karageorgiou
Behavioral & Sleep Neurologist
Elisa França Resende, MD, PhD
Neurologist
Andrea Slachevsky, MD, PhD
Rob Whelan, PhD
Professor in Psychology
Jonathan Adrián Zegarra Valdivia, PhD
Neuroscientist
Faheem Arshad, MD, DM, FICN
Neurologist
Carlos Coronel, PhD
Neuroscientist
Josefina Cruzat, PhD, MS
Neuroscientist
Damián Dellavale, PhD
Scientific Researcher
Laz Eze, MBBS, MPH, FAPH
Physician, Public Health Policy and Management Specialist
Tavia Evans, BSc, MSc, PhD
Neuroscientist
Temitope Farombi, MBBS, PhD, FMCP (Neurol)
Neurologist
Sol Fittipaldi, PhD
Neuroscientist
Adolfo M. García, PhD
Neuroscientist
Maria Eugenia Godoy, MSc
Project Manager
Chukwuanugo Ogbuagu, MBBS, PhD, MWACP
Public Health Physician and Lecturer
Maira Okada de Oliveira, PhD
Neuropsychologist
Stefanie Piña Escudero, MD
Geriatrician
Pablo Alexander Reyes Gavilan, PhD
Neuropsychologist
Hernando Santamaría-García, MD, MSc, PhD
Psychiatrist and Researcher
Jennifer Yokoyama, PhD
Associate Professor of Neurology
Bruce Miller, MD
Founding Director, University of California, San Francisco
Cyprian Mostert, MSc, MM, PhD
Economist
Brian Lawlor, MD, FRCPI, FRCPsych, MRIA
Founding Director, Trinity College Dublin
Harris Eyre
Neuroscientist
Sandra Báez, PhD, MS
Neuroscientist, Neuropsychologist
Claudia Duran-Aniotz, MSc, PhD
Neurobiologist
Agustín Ibáñez, PhD
Neuroscientist
