BackgroundCognitive impairment in late−life depression (LLD) is considered to be caused by neurodegenerative changes. Elevated homocysteine (Hcy) levels may be linked to cognitive abnormalities associated with LLD. The important role of white matter (WM) damage in cognitive impairment and pathogenesis in patients with LLD has been widely reported. However, no research has explored the interrelationships of these features in patients with LLD.ObjectiveThe goal of the study was to examine the interrelationship between Hcy levels, cognition, and variations in WM microstructure detected by diffusion tensor imaging (DTI) in patients with LLD.MethodsWe recruited 89 healthy controls (HCs) and 113 patients with LLD; then, we measured the plasma Hcy levels of participants in both groups. All individuals performed a battery of neuropsychological tests to measure cognitive ability. Seventy-four patients with LLD and 68 HCs experienced a DTI magnetic resonance imaging (MRI) scan.ResultsPatients with LLD showed significantly lower fractional anisotropy (FA) values in the bilateral inferior longitudinal fasciculus than those of healthy participants. Only in LLD patients was Hcy concentration inversely associated to FA values in the forceps minor. Finally, multiple regression analyses showed that an interaction between Hcy levels and FA values in the right cingulum of the cingulate cortex and right inferior longitudinal fasciculus were independent contributors to the executive function of patients with LLD.ConclusionOur results highlight the complex interplay between elevated homocysteine levels and WM abnormalities in the pathophysiology of LLD-related cognitive impairment, consistent with the neurodegeneration hypothesis.