Long-term brain volume trajectories and lifestyle associations in cognitively normal adults: the BRAIN-STRIDE study

Brain ageing is a major determinant of cognitive health, yet the extent of inter-individual variability in structural trajectories and its links to lifestyle factors remain incompletely understood. We conducted a single-centre, prospective longitudinal cohort study within an urban academic health screening programme in Japan (November 2006 to April 2021), with up to 15 years of follow-up. Among 10 209 individuals who underwent screening, those with more than 10 years of serial visits were eligible; 186 participants were excluded for major intracranial findings, 3 for cognitive decline during follow-up and 3 for contraindications or ineligibility, yielding 653 cognitively normal adults [207 women (31.6%); mean (SD) age at baseline, 55.1 (9.3) years]. Participants underwent serial magnetic resonance imaging and Mini-Mental State Examination, along with baseline assessments of lifestyle and vascular risk factors including body mass index, blood pressure, smoking exposure and lipid profile. Annual percentage change in whole-brain and regional volumes was estimated using linear mixed-effects models after harmonization for scanner effects, and participants were categorized as rapid atrophy, typical, or atrophy-resistant based on percentile thresholds. Across 7915 MRI scans, whole-brain volume decline accelerated from 0.24% per year in the 40s to 0.44% per year in the 70s. Individuals classified as having rapid atrophy in their 40s exhibited rates of decline of 0.46% per year, comparable to population averages in the 70s, whereas atrophy-resistant individuals in their 70s demonstrated rates as low as 0.27% per year. Faster whole-brain atrophy was associated with higher body mass index [β = 0.027; 95% confidence interval (CI), 0.0058-0.049], greater smoking exposure (β = 0.032; 95% CI, 0.012-0.053), elevated diastolic blood pressure (β = 0.044; 95% CI, 0.021-0.067) and higher low-density lipoprotein cholesterol (β = 0.043; 95% CI, 0.021-0.065) (all P < 0.01). Utilizing an uncommonly long and densely sampled longitudinal design, this study demonstrates that structural brain ageing among cognitively normal adults follows highly heterogeneous trajectories, spanning from marked decline to near-complete resistance. Modifiable lifestyle and vascular risk factors were associated with faster atrophy, supporting opportunities for risk stratification and targeted prevention strategies.