Abstract
<title>Abstract</title> <p>Background Olfactory dysfunction is among the earliest features of neurodegenerative diseases and has been associated with poorer cognitive performance in cross-sectional studies. However, whether olfactory function predicts the trajectory of cognitive decline over time, and whether this trajectory is mediated through regionally specific brain structural change has not been established in a prospective longitudinal cohort. Objectives The aims of this study were twofold: first, to investigate the association between olfactory function at baseline and both MRI structural change and cognitive decline; second, to examine if longitudinal MRI structural change mediates the olfaction-cognition association. Methods We examined 847 community-dwelling adults aged 70–90 years from the Sydney Memory and Ageing Study, followed over six years with repeated neuropsychological assessments (0, 2, 4, and 6 years) and structural MRI (0, 2, and 6 years). Olfactory function was tested using Brief Smell Identification Test at baseline. The association between baseline olfactory function, longitudinal MRI structural change, and cognitive decline were assessed using linear mixed models across 200 imputed datasets. Mediation by longitudinal MRI change was tested across eight a priori candidate structures, using a two-stage product-of-coefficients approach and a joint latent growth curve mediation model. Results Higher olfaction scores were significantly associated with slower cognitive decline in global cognition (β = 0.0081, 95% CI: 0.0020 to 0.0141, p = 0.009), executive function, attention/processing speed and memory. The two-stage mediation analysis identified a statistically significant indirect effect on cognitive decline mediated through hippocampal atrophy (global cognition: ab = 0.0012, 95% CI: 0.0003 to 0.0022, p = 0.009) and inferior lateral ventricular enlargement (global cognition: ab = 0.0009, 95% CI: 0.0001 to 0.0018, p = 0.028). The latent growth curve mediation model produced directionally consistent but attenuated estimates. Higher BSIT scores were also significantly associated with slower hippocampal atrophy (β = 10.89 mm³/year, PFDR = 0.001) and slower inferior lateral ventricular expansion (β = −10.71 mm³/year, PFDR = 0.015) in the MRI trajectory analysis. Conclusions Higher baseline olfaction scores are associated with slower cognitive decline and slower medial temporal structural change. Trajectory-based analyses suggested this association may be partially mediated by the rate of hippocampal atrophy. These findings are consistent with a medial temporal neurodegeneration pathway linking olfactory dysfunction to cognitive deterioration in older age. Olfactory function may be a useful marker of cognitive ageing, though its clinical utility requires validation in biomarker-informed cohorts.</p>