Individual variations in ‘brain age’ relate to early-life factors more than to longitudinal brain change

Abstract

<i>Brain age</i> is a widely used index for quantifying individuals' brain health as deviation from a normative brain aging trajectory. Higher-than-expected <i>brain age</i> is thought partially to reflect above-average rate of brain aging. Here, we explicitly tested this assumption in two independent large test datasets (UK Biobank [main] and Lifebrain [replication]; longitudinal observations ≈ 2750 and 4200) by assessing the relationship between cross-sectional and longitudinal estimates of <i>brain age. Brain age</i> models were estimated in two different training datasets (n ≈ 38,000 [main] and 1800 individuals [replication]) based on brain structural features. The results showed no association between cross-sectional <i>brain age</i> and the rate of brain change measured longitudinally. Rather, <i>brain age</i> in adulthood was associated with the congenital factors of birth weight and polygenic scores of <i>brain age,</i> assumed to reflect a constant, lifelong influence on brain structure from early life. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.