Overview of the study workflow.

a, Population cohorts (UK Biobank and IMAGEN) and data sources (brain imaging, biological aging biomarkers, cognitive functions, genomic data) involved in this study. b, Brain aging patterns were identified using longitudinal trajectories of the whole brain GMV, and associations between brain aging patterns and other measurements (biological aging, cognitive functions and PRS of major neuropsychiatric disorders) were investigated. c, Mirroring patterns between brain aging and brain development was investigated using z-transformed brain volumetric change map and gene expression analysis.

Global (a) and selected regional (b, c) cortical gray matter volume rate of change among participants with brain aging patterns 1 (red) and 2 (blue).

Rates of volumetric change for total gray matter and each ROI were estimated using GAMM, which incorporates both cross-sectional between-subject variation and longitudinal within-subject variation from 40,921 observations and 37,013 participants. Covariates include sex, assessment center, handedness, ethnic, and ICV. Shaded areas around the fit line denotes 95% CI.

Distributions of biological aging biomarkers (leucocyte telomere length (LTL) and PhenoAge) among participants with brain aging patterns 1 and 2.

Boxes represent the interquartile range (IQR), lines within the boxes indicate the median, and whiskers indicate potential outliers (values outside of the 1.5 IQR range). Two-sided P values were obtained by comparing LTL or PhenoAge19 between brain aging patterns using unadjusted multivariate linear regression models. Results remained significant when adjusting for sex, age, ethnic, BMI, smoking status and alcohol intake frequency in the LTL model20 and sex, age, ethnic, BMI, smoking status, alcohol frequency and education years in PhenoAge model. Stars indicate statistical significance after Bonferroni correction. ****: p <= 0.0001, *: p <= 0.05.

Effect size (Cohen’s D or odds ratio) for comparing the cognitive functions between participants with brain aging patterns 1 and 2.

Results were adjusted such that negative Cohen’s D and Odds Ratio less than 1 indicate worse cognitive performances in brain aging pattern 2 compared to pattern 1. Width of the lines extending from the center point represent 95% confidence interval. Two-sided P values were obtained using both unadjusted and adjusted (for sex, age, and TDI, education and income) multivariate regression models. Stars indicate statistical significance after FDR correction for 11 comparisons. ****: p <= 0.0001, ***: p <= 0.001, **: p <= 0.01, ns: p > 0.05.

Participants with accelerated brain aging (brain aging pattern 2) had significantly increased genetic liability to ADHD and delayed brain development.

Polygenic risk score (PRS) for ADHD, ASD, AD, PD, BIP, MDD, SCZ and delayed brain development (unpublished GWAS) were calculated at different p-value thresholds from 0.005 to 0.5 at an interval of 0.005. Vertical axis represents negative logarithm of P values comparing PRS in brain aging pattern 2 relative to pattern 1. Red horizontal dashed line indicates FDR corrected P value of 0.05. Colors represent traits and dots within the same color represent different p value thresholds. The trigonometric symbol indicates the average PRS across all p-value thresholds for the same trait.

Genome-wide association study (GWAS) identified 6 independent SNPs associated with accelerated brain aging.

Total GMV at 60 years old was estimated for each participant using mixed effect models allowing for individualized baseline GMV and GMV change rate, and was used as the phenotype in the GWAS. a, At genome-wide significance level (P=5e-8, red dashed line), rs10835187 and rs7776725 loci were identified to be associated with accelerated brain aging. b, Quantile–quantile plot showed that the most significant P values deviate from the null, suggesting that results are not unduly inflated.

The “last in, first out” mirroring patterns between brain development and brain aging.

a, The annual percentage volume change (APC) was calculated for each ROI and standardized across the whole brain in adolescents (IMAGEN, left) and mid-to-late aged adults (UK Biobank, right), respectively. For adolescents, ROIs of in red indicate delayed structural brain development, while for mid-to-late aged adults, ROIs in blue indicate accelerated structural brain aging. b, Estimated APC in brain development versus early aging (55 years old, left), and versus late aging (75 years old, right). ROIs in red indicate faster GMV decrease during brain aging and slower GMV decrease during brain development, i.e., stronger mirroring effects between brain development and brain aging. c, Mirroring patterns between brain development and brain aging were more manifested in participants with accelerated aging (brain aging pattern 2).

Functional enrichment of gene transcripts significantly associated with delayed brain development and accelerated brain aging.

a, 990 genes were spatially correlated with the first PLS component of delayed structural brain development, and were enriched for trans-synaptic signal regulation, forebrain development, signal release and cAMP signaling pathway. b, 2,293 genes were spatially correlated the first PLS component of accelerated structural brain aging, and were enriched for macroautophagy, pathways of neurodegeneration, establishment of protein localization to organelle and histone modification. Size of the circle represents number of genes in each term and P values were corrected using FDR for multiple comparisons.