Lamellar Normative Modelling of the Hippocampus Across the Human Lifespan

Abstract The hippocampus is a central hub of human memory and cognition and is closely associated with brain disorders. Studies have shown that it exhibits complex structural variation across the lifespan, yet the details of hippocampal morphology changes remain poorly understood. Here, we establish norms over the hippocampal geometry that resolve lamellar morphology and map lifespan trajectories across more than 27,000 individuals from 158 scanning sites. Hippocampal geometry shows spatially non-uniform developmental and ageing patterns across the lifespan, with lamellar thickness, width and length following dissociable trajectories. Across multiple brain disorders, this representation reveals localized and heterogeneous alterations beyond conventional subfield-level summaries, and uncovers a dichotomy in disease-associated patterns, with neurodegenerative conditions and schizophrenia showing predominant atrophy, whereas some other disorders exhibit focal or regionally selective hypertrophy. Transfer to a longitudinal Alzheimer’s Disease Neuroimaging Initiative cohort further supports out-of-sample generalization of our approach and enables individual-level tracking and conversion risk stratification. Overall, this work establishes a population-scale geometric reference for the hippocampus, extends normative brain mapping from coarse regional phenotypes to anatomically organized subcortical structure, and enables anatomically grounded characterization of disease-related alterations and individual-level deviation mapping, providing a principled basis for understanding and stratifying brain disorders across the lifespan in health and disease. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵# Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf Update the author list. Add Zhiyuan Liu, which is not included in the previous version.