Causal association between allostatic load and accelerated white matter brain aging: findings from the UK Biobank.

White matter (WM) brain age, a neuroimaging-derived biomarker indicating WM microstructural changes, helps predict dementia and neurodegenerative disorder risks. The cumulative effect of chronic stress on WM brain aging remains unknown. In this study, we assessed cumulative stress using a multi-system composite allostatic load (AL) index based on inflammatory, anthropometric, respiratory, lipidemia, and glucose metabolism measures, and investigated its causal association with WM brain age gap (BAG), computed from diffusion tensor imaging data using a machine learning model, among 22 951 European ancestries aged 40 to 69 (51.40% women) from UK Biobank. Linear regression, Mendelian randomization, along with inverse probability weighting and doubly robust methods, were used to evaluate the impact of AL on WM BAG adjusting for age, sex, socioeconomic, and lifestyle behaviors. We found increasing one AL score unit significantly increased WM BAG by 0.29 years in association analysis and by 0.33 years in Mendelian randomization causal analysis. The age- and sex-stratified analysis showed consistent results among participants 45-54 and 55-64 years old, with no significant sex difference. This study demonstrated that higher chronic stress caused accelerated brain aging, highlighting the importance of stress management in reducing dementia and neurodegenerative disease risks.