Hippocampal Asymmetry Captures Non Amyloid Related Risk of Memory Decline and Clinical Progression

BackgroundHippocampal atrophy is a key marker of Alzheimers disease (AD)-related neurodegeneration; however, hippocampal volume alone may not fully capture heterogeneity in cognitive decline. Hemispheric hippocampal asymmetry may provide complementary information, but its prognostic value for cognitive decline and clinical progression remains unclear. MethodsWe studied 1,142 dementia-free participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) with available baseline structural MRI, cerebrospinal fluid (CSF) amyloid-{beta} (A{beta}42) and phosphorylated tau (p-tau-181), and longitudinal cognitive follow-up. Total hippocampal volume (left + right) and hemispheric asymmetry (absolute left-right volumetric difference) were modeled simultaneously. Linear mixed-effects models examined associations with baseline performance and longitudinal change across memory, language, executive, and visuospatial domains. Cox proportional hazards models assessed risk of clinical progression to clinical dementia over up to 10 years of follow-up. All analyses adjusted for age, sex, education, APOE {varepsilon}4 status, and CSF biomarkers, with stratification by amyloid status. ResultsThe study cohort included 546 women (47.8%), with a mean age of 72.54 {+/-} 6.98 years. Larger total hippocampal volume was consistently associated with better baseline performance and slower decline across all four cognitive domains, independent of amyloid and tau biomarkers. In contrast, greater hippocampal asymmetry was selectively associated with worse baseline memory performance and faster memory decline, independent of total hippocampal volume. In amyloid-stratified analyses, total hippocampal volume showed broad associations with cognition across all four domains among amyloid-positive participants and more limited, domain-specific associations among amyloid-negative participants, whereas hippocampal asymmetry was associated with memory only in amyloid-negative individuals. Regarding clinical progression to dementia, smaller total hippocampal volume was associated with higher risk of progression in the overall cohort and within both amyloid groups. In contrast, hippocampal asymmetry was associated with progression risk only among amyloid-negative individuals (hazard ratio per SD increase = 1.31, 95% CI: 1.03-1.65). ConclusionsHippocampal total volume and asymmetry capture distinct aspects of neurodegeneration, with asymmetry providing additional prognostic information for memory decline and clinical progression in participants without detectable amyloid pathology.