Cerebellar White Matter Microstructure Is Associated With Age, Cerebrospinal Fluid Amyloid Beta Levels, and Cognition in Cognitively Unimpaired Older Adults

Abstract

Structural changes in the cerebellum contribute to cognitive decline due to aging and Alzheimer's disease (AD). However, it is unclear whether age and AD pathology are associated with structural alterations in the cerebellum among cognitively unimpaired individuals and how these alterations relate to cognition. This study examined the association of age and cerebrospinal fluid (CSF) AD biomarkers (amyloid beta [Aβ₄₂/Aβ₄₀], phosphorylated tau [p-tau₁₈₁]) with cerebellar gray matter (GM) and white matter (WM) volumes and cerebellar WM microstructure, measured via magnetic resonance imaging (MRI) among 176 cognitively unimpaired middle-aged and older adults (mean age = 66.70, range = 34-89). Cognition was measured with executive function and visuospatial composite scores. Older age was associated with lower cerebellar GM and WM volumes (ps < 0.01) and greater mean diffusivity (MD) in the cerebellar peduncles (p < 0.01). In contrast, more abnormal Aβ levels were associated with lower MD in three regions of interest, including the middle cerebellar peduncle (MCP, p < 0.01), a composite of superior, middle, and inferior peduncles (p < 0.05), and within-cerebellar WM (p < 0.05). Patterns were similar when comparing biomarker positive versus negative groups, particularly for the MCP. Further, lower MD in the peduncles and cerebellar WM was associated with better executive function and visuospatial composite scores (ps < 0.05), whereas cerebellar volumetric measures were not related to cognition. Results suggest that older age is associated with microstructural and volumetric cerebellar GM and WM alterations. In contrast, Aβ levels are associated with WM microstructural properties in cognitively unimpaired individuals. These findings highlight the importance of cerebellar WM microstructure to cognition and are consistent with, and expand on, previous reports that have linked more abnormal amyloid levels to WM microstructure in cerebral tracts. They also suggest that cerebellar WM alterations may be markers of preclinical AD.

Keywords: Alzheimer's disease; amyloid beta; cerebellum; cerebrospinal fluid; cognition; diffusion weighted imaging; white matter microstructure.