Normative modeling of brain structure in healthy individuals elucidates cortical atrophy patterns in Alzheimer's disease

Normative modeling in neuroscience aims to characterize interindividual variation in brain phenotypes and establish reference ranges, or brain charts, against which individuals can be compared. Normative models are typically limited to coarse spatial scales due to computational constraints, limiting their spatial specificity. Furthermore, dependence on fixed parcellation atlases limits their adaptability to alternative parcellation schemes. To overcome these key limitations, we propose spectral normative modeling (SNM), which leverages brain eigenmodes to efficiently generate normative ranges for arbitrarily defined regions of interest. Training SNM on over 78,000 healthy brain scans, we generate accurate lifespan thickness growth charts across different spatial scales, from millimeters to the whole brain. These charts reveal three principal thickness growth gradients, aligning neurotypical cortical change with established anatomical, genetic, and functional hierarchies. We further demonstrate SNM's utility by elucidating high-resolution individual cortical atrophy patterns that characterize the heterogeneous expression of neurodegeneration in Alzheimer's disease. SNM lays the groundwork for a new generation of spatially precise brain charts, offering substantial potential to drive advances in individualized precision medicine.