Hippocampal microstructure, but not macrostructure, mediates age differences in episodic memory.

Introduction: Separate unimodal magnetic resonance imaging (MRI) literatures have shown that hippocampal gray matter macrostructure (volume) and microstructure (diffusion) decline with age and relate to episodic memory performance, with multimodal MRI studies reporting that episodic memory may be better explained by a combination of these metrics. However, these effects are often assessed independent of age or only within older adults and therefore do not address whether these distinct modalities explain variance in (i.e, mediate) the effect of age on episodic memory. Methods: Here, we simultaneously examined the unique and joint contribution of hippocampal volume and diffusion to age-related differences in episodic memory in 83 younger and 61 older adults who underwent a T1- and diffusion-weighted MRI and completed the Rey Auditory Verbal Learning Test. Results: As expected, older age was significantly related to smaller volume and higher diffusion (intracellular, dispersion, and free) in bilateral hippocampus and to worse episodic memory performance (immediate and delayed free recall, recognition). Structural equation modelling revealed that the age-memory relationship was significantly mediated by hippocampal diffusion, but not volume. A non-significant influential indirect effect further revealed that the structural metrics did not jointly mediate the age-memory relationship. Discussion: Together, these findings indicate that hippocampal microstructure uniquely contributes to age-related differences in episodic memory and suggest that volume and diffusion capture distinct neurobiological properties of hippocampal gray matter.