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 anterior-posterior subregional hippocampal volume differences among ADc, SNAP, and biomarker-negative participants, and their associations with CSF biomarkers and clinical presentation. METHODS: Data from 1242 participants in the Alzheimer's Disease Neuroimaging Initiative were analyzed. Biomarker-negative participants (n = 234) had normal CSF Aβ42 (≥ 192 pg/ml), total tau (< 93 pg/ml), and phosphorylated tau at threonine 181 (< 23 pg/ml). ADc individuals (n = 784) had abnormal Aβ42, and SNAP (n = 224) showed normal Aβ42 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 biomarker-negative participants (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 biomarker-negative participants 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.