Dissecting the sex-dependent muscle-brain axis: Hippocampal subfields mediate the association between grip strength and cognition in amnestic mild cognitive impairment

BACKGROUND: Grip strength has been increasingly recognized as a potential indicator of cognitive decline and is closely associated with hippocampal structure. However, whether this muscle-brain relationship differs by sex among individuals with amnestic mild cognitive impairment (aMCI) remains unclear. OBJECTIVE: To explore sex-specific relationships among grip strength, hippocampal subfield volumes and cognitive function in aMCI. METHODS: This case-control study enrolled 144 aMCI patients and 84 healthy controls, demographic, neuropsychological, grip-strength data and 3.0 T MRI images were collected. Principal component analysis (PCA), multivariate regression, Pearson correlation and mediation analyses were performed. RESULTS: Significant differences were found in the volumes of 15 hippocampal subfields, education level, right grip strength and cognitive scores. A bilateral grip strength related factor extracted by PCA was significantly associated with global cognition, memory, language, executive function and emotional status. Sex-stratified analyses revealed sex-specific correlations between grip strength, cognitive scores and hippocampal subfield volumes. Right hippocampal fissure partially mediated (20.33%) the relationship between right grip strength and ACE-III scores in males. CONCLUSIONS: Grip strength was correlated with hippocampal subfield integrity and cognitive function in a sex-specific manner. These observations illustrated an associative pathway linking muscular strength to cognitive vulnerability, with grip strength representing a potential observational marker for early-stage cognitive risk.