Differential atrophy along the longitudinal axis of the hippocampus in Alzheimer’s Disease and Suspected Non-Alzheimer’s Disease Pathophysiology (SNAP)

Purpose: Cerebrospinal fluid (CSF) biomarkers are increasingly used to support Alzheimer’s disease (AD) diagnosis: Alzheimer’s Disease continuum (ADc) is defined by abnormal amyloid-beta (Aβ), while Suspected Non-AD Pathophysiology (SNAP) refers to normal Aβ with elevated tau. Given the differential properties along the hippocampal longitudinal axis, this study aimed to evaluate antero-posterior subregional hippocampal volume differences among ADc, SNAP, and controls, and their associations with CSF biomarkers and clinical presentation. Methods: Data from 1242 participants in the Alzheimer’s Disease Neuroimaging Initiative were analyzed. Controls (n=234) had normal CSF Aβ (≥192 pg/ml), total tau (<93 pg/ml), and phosphorylated tau (<23 pg/ml). ADc individuals (n=784) had abnormal Aβ, and SNAP (n=224) showed normal Aβ with elevated tau. T1-weighted MRI scans were used to segment the hippocampus into anterior, intermediate, and posterior subregions. Controlling for age, sex, and multiple comparisons, groups were compared using one-way ANOVA, and Pearson correlation coefficients were calculated to assess the relationships between volumetric variables and age, CSF biomarkers, or neuropsychological scores. Results: ADc individuals showed significantly lower total and subregional hippocampal volumes compared with SNAP and controls (P<0.001). Normalized volumes to total ipsilateral hippocampal volume revealed greater posterior atrophy (P<0.001) and relatively higher anterior volume (P<0.01) in ADc. SNAP and controls showed stronger correlations between hippocampal volumes and age. Several subregional hippocampal volumes correlated with CSF biomarkers, cognitive performance, neuropsychiatric symptoms, and functional impairment. Conclusion: This study reveals distinct patterns of hippocampal atrophy in ADc and SNAP, enhancing our understanding of their differential pathophysiology and associated clinical features.