Individual variations in 'brain age' relate to early-life factors more than to longitudinal brain change.

Brain age is a widely used index for quantifying individuals' brain health as deviation from a normative brain aging trajectory. Higher-than-expected brain age 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 brain age. Brain age 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 brain age and the rate of brain change measured longitudinally. Rather, brain age in adulthood was associated with the congenital factors of birth weight and polygenic scores of brain age, 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.

Scientists who study the brain and aging are keen to find an effective way to measure brain health, which could help identify people at risk for dementia or memory problems. One popular marker is 'brain age'. This measurement uses a brain scan to estimate a person's chronological age, then compares the estimated brain age to the person's actual age to determine whether their brain is aging faster or slower than expected for their age. However, since brain age relies on one brain scan taken at one point in time, it is not clear whether it really measures brain aging or if it might capture brain differences that have been present throughout the individual's life. Studies comparing individual brain scans over several years would be necessary to know for sure. Now, Vidal-Piñeiro et al. show that the brain-age measurement does not reflect faster brain aging. In the experiments, the researchers compared repeated brain scans of thousands of individuals over 40 years of age. The experiments showed that deviations from normative brain age detected in a single scan reflected early life differences more than changes in the brain over time. For example, people with older-looking brains were more likely to have had a low birth weight or to have a combination of genes associated with having an older looking brain. Vidal-Piñeiro et al. show that brain age mostly reflects a pre-existing brain condition rather than brain aging. The experiments also suggest that genetics and early brain development likely have a strong impact on brain health throughout life. Future studies trying to test or develop brain-aging measurements should use serial measurements to track brain changes over time.

The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan.

Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single-nucleotide polymorphisms-based analyses of 38,127 cross-sectional MRIs showed a similar pattern of genetic volume-volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization.