Altered Hippocampal Structure-Function Coupling and Brain-Cognition Aging Profile in Mild Cognitive Impairment

Abstract

Hippocampal atrophy and altered functional connectivity are prominent features of mild cognitive impairment (MCI), yet their relationships and joint contribution to cognitive impairment remain unclear. We evaluated multidomain cognitive-sensorimotor performance, whole-brain gray matter atrophy patterns, associated functional connectivity, and their coupling in MCI and HC. We conducted this cross-sectional study in 25 clinically diagnosed amnestic and non-amnestic MCI patients and 15 age- and education-matched healthy controls (HC). Participants (57-81 years old) completed a battery assessing general cognition, executive functions, attention, speech-in-noise perception, manual dexterity, and balance, combined with structural and resting-state functional magnetic resonance imaging. Among the 25 MCI patients, 8 (32%) presented with amnestic MCI, 15 (60%) with non-amnestic MCI, and 2 (8%) with subjective cognitive decline. Linear mixed models revealed that semantic fluency (g = 0.74) was the largest discriminator of MCI, followed by attention (g = 0.61), phonemic fluency (g = 0.59), and speech-in-noise perception (g = 0.56). Voxel-based morphometry showed bilateral hippocampal and anteromedial cerebellar gray matter atrophy in MCI. Seed-based functional connectivity analyses indicated that atrophy was not uniformly associated with reduced connectivity. Cortico-subcortical hypoconnectivity emerged only in networks associated with left hippocampal atrophy in MCI compared with HC. Network-based analyses showed disrupted brain-behavior coupling and a stronger detrimental influence of age in MCI than in HC. These findings confirm the critical role of hippocampal structure-function relationships in multidomain MCI symptoms. A decoupled brain-cognition aging profile suggests that multimodal indices integrating hippocampal structure, connectivity, and behavioral performance may strengthen MCI diagnosis.