Mapping hippocampal subfield heterogeneity across neurological disorders by normative modeling

The hippocampus serves as a hub of cognition, and its subfields differ in their susceptibility to aging and neurological disorders. Here, we established normative references for hippocampal and subfield volumes using 3D T1-weighted magnetic resonance imaging (MRI) scans from 34,789 healthy individuals (range from 4 to 85 years), revealing varied peak ages (27.4-40.1 years) across subfields. We then mapped the hippocampus and its subfields across various neurological disorders (mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease, cerebral small vessel disease, and multiple sclerosis) by deriving personalized deviation (centile) scores from these references in 3,521 patients. These centile scores captured disease-specific hippocampal abnormalities, supported disease classification, and were associated with cognitive performance, longitudinal cognitive outcomes, and disease progression across disorders. Finally, a personalized hippocampal health report was developed to facilitate clinical translation. These findings demonstrate the value of hippocampal and subfield normative references for personalized diagnosis, cognitive assessment, and prognostic evaluation across neurological diseases. This study establishes age-specific reference ranges for hippocampal subfields and shows that personalized deviations from these norms can distinguish neurological disorders and help assess cognition and disease progression.