Dynamic long-term modulation of cognition, brain structure and covariance networks in mild cognitive impairment due...

Whether donepezil exerts long-term efficacy in mitigating cognitive decline, preserving brain structure, and restoring impaired structural covariance networks in patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) remains controversial.

This study aimed to characterize the longitudinal dynamic alterations in cognition, brain morphology, and structural covariance network topology in AD-MCI patients receiving continuous 36-month donepezil treatment, thereby elucidating the long-term modulatory effects of donepezil on AD progression.

Cross-sectional analysis included 92 normal controls (NC) and 107 AD-MCI patients to identify baseline abnormalitiesin cognitive performance, brain morphological parameters, global topological features, and nodal metrics of individual gray matter covariance networks. Subsequently, 35 AD-MCI patients who completed 36-month continuous donepezil treatment were retrospectively enrolled to explore the therapeutic modulation of donepezil on the aforementioned abnormal indicators. Linear and piecewise linear mixed-effects models were employed to quantify longitudinal changes.

AD-MCI patients showed left hippocampus (including subfields) atrophy and widespread structural covariance network impairment at baseline. During treatment, significant time main effects were observed in MMSE scores and the volume of the left hippocampus and multiple subfields, both of which continued to show progressive decline, with accelerated deterioration between 12 and 18 months. Global topological metrics stabilized after initial short-term improvement, while right hippocampus nodal metrics were significantly enhanced.

Donepezil treatment in AD-MCI patients represents a dynamic therapeutic process: it elicits transient short-term improvement of global brain network topology but confers only modest long-term benefits, with insufficient evidence supporting sustained, impactful neuroprotective effects. This study provides novel multi-level longitudinal evidence describing the neuroimaging changes underlying donepezil's modulation of AD progression.