Sex-Dependent Age Trajectories of Subcortical Brain Structures: Analysis of Large-Scale Percentile Models and Shape Morphometry

Modeling of structural brain variation over the lifespan is important to better understand factors contributing to healthy aging and risk for neurological conditions such as Alzheimers disease. Even so, we lack normative data on brain morphometry across the adult lifespan in large, well-powered samples. Here, in a large population-based sample of 26,440 adults from the UK Biobank (age: 44-81 yrs.), we created normative percentile charts for MRI-derived subcortical volumes. Next, we investigated associations between these morphometric measures and the strongest known genetic risk factor for late-onset Alzheimers disease (APOE genotype) and mapped the spatial distribution of age-by-sex interactions using computational surface mesh modeling and shape analysis. Vertex-wise shape mapping supplements traditional gross volumetric approaches to reveal finer-grained variations across functionally important brain subcompartments. Normative curves revealed volumetric loss with age, as expected, for all subcortical brain structures except for the lateral ventricles, which expanded with age. Surprisingly, no volumetric associations with APOE genotype were detected, despite the very large sample size. Age-related trajectories for volumes differed in women versus men, and surface-based statistical maps revealed the spatial distribution of the age-by-sex interaction. Subcortical volumes declined faster in men than women over the full age range, but after age 60, fewer structures showed sex-dependent trajectories, indicating similar volumetric changes in older men and women. Large-scale statistical modeling of age effects on brain structures may drive new insights into individual differences in brain aging and help to identify factors that promote healthy brain aging and risk for disease.