Abstract
BACKGROUND: Early degeneration of the cholinergic nucleus basalis of Meynert contributes to cognitive decline in Alzheimer's disease (AD). Microstructural damage in downstream cholinergic tracts-the cingulum bundle (CGC), entorhinal cortex (EC), and uncinate fasciculus (UNC)-often precedes volumetric atrophy. While cholinesterase inhibitors (ChEIs) can preserve cortical and hippocampal volume, their influence on white-matter integrity is unclear. OBJECTIVE: To determine whether ChEIs slow microstructural decline in four cholinergic tracts (CGC, EC, UNC, posterior thalamic radiation [PTR]) in mild cognitive impairment (MCI), and whether baseline cognitive status modulates this effect. METHODS: Diffusion-tensor imaging from the Alzheimer's Disease Neuroimaging Initiative was analyzed in 46 MCI participants receiving donepezil or rivastigmine and 62 untreated MCI controls, each scanned serially over two years. Fractional anisotropy (FA) and mean diffusivity (MD) indexed tract integrity. Linear mixed-effects models tested time × medication × baseline cognition (ADAS-Cog13) interactions, adjusting for age, sex, APOE ε4, and white-matter hyperintensity burden. RESULTS: Across groups, CGC showed progressive degeneration (FA↓, MD↑; p < 0.001). Significant three-way interactions emerged for MD in bilateral CGC, FA in right EC, and MD in left PTR (all p < 0.01). ChEI users with milder baseline impairment (lower ADAS-Cog13) exhibited attenuated FA loss and MD increase, indicating slower microstructural decline; those with greater initial impairment derived minimal benefit. No medication effect was detected in UNC. CONCLUSIONS: ChEIs confer tract-specific, stage-dependent protection of cholinergic white matter, particularly in early MCI. The findings underscore the value of initiating ChEI therapy before substantial cognitive deterioration and highlight the need for stage-tailored interventions aimed at preserving white-matter integrity in prodromal AD.