Association of Cholinergic Stimulation with Improved Functional Performance and Neurotrophic Markers in Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is frequently accompanied by early impairment in gait and postural control. Whether commonly prescribed cognitive therapies differentially influence physical function and neurotrophic signaling remains unclear. We followed 99 older adults with MCI for six months while receiving either the cholinergic agent Donepezil (n = 47, age = 68.3 ± 4.1 years) or the glutamatergic modulator Memantine (n = 52, age = 70.1 ± 3.9 years). Postural balance and gait speed were assessed using the Short Physical Performance Battery. Plasma brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured. Donepezil treatment improved postural balance (Cohen's d = 0.30) and gait speed (d = 0.45), whereas Memantine produced no meaningful changes (d < 0.20 for both outcomes). Repeated-measures ANOVA demonstrated significant Time × Treatment interactions for balance (F(1,97) = 5.9, p < 0.05) and gait speed (F(1,97) = 6.4, p < 0.05). Plasma BDNF increased by approximately 22% (d = 0.46) and GDNF by 19% (d = 0.42) following Donepezil, with no significant biomarker changes in the Memantine group. In the Donepezil group, changes in BDNF correlated with improvements in balance (r2 = 0.13, p = 0.012) and gait speed (r2 = 0.12, p = 0.018), while GDNF changes correlated with balance (r2 = 0.10, p = 0.032) and gait speed (r2 = 0.19, p = 0.002). Multivariate regression analyses demonstrated independent associations of BDNF and GDNF with balance and selected functional outcomes after adjustment for confounders. Donepezil is associated with clinically meaningful improvements in mobility in MCI, accompanied by enhanced neurotrophic support. These findings are consistent with a relationship between cholinergic stimulation, motor function, and neurotrophic pathways in MCI.