Alzheimer-related individual factors modulate effects of transcranial direct current stimulation strength on white matter integrity in mild cognitive impairment.

Transcranial direct current stimulation (tDCS) is a promising non-invasive intervention for mild cognitive impairment (MCI). This prospective study investigated the relationship between optimized electrical field (EF) strength of tDCS and white matter (WM) microstructural changes in 55 individuals with MCI. Magnetic resonance imaging (MRI)-based computational modeling was used to optimize EF strength targeting the left dorsolateral prefrontal cortex (DLPFC). Diffusion tensor imaging (DTI) assessed WM integrity through fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Higher EF strength was significantly associated with increased FA and reduced MD and RD in specific left-lateralized tracts, including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus. These EF-dependent WM changes were moderated by Alzheimer's disease (AD)-related factors. Greater WM plasticity was observed in Aβ-positive individuals, APOE ε4 non-carriers, and BDNF Met non-carriers. Moreover, APOE ε4 status significantly moderated the relationship between EF strength and executive function; in non-carriers, stronger EF strength was associated with improved Stroop performance, potentially reflecting enhanced WM integrity in the right superior longitudinal fasciculus. However, no significant associations were observed between EF-sensitive tracts and short-term cognitive changes in the full sample, suggesting that structural modifications may precede functional improvements or require longer follow-up. These findings emphasize the importance of individual AD-related factors in shaping neuromodulatory responses. They also support the need for longitudinal, sham-controlled studies to clarify the clinical implications of EF strength in personalized tDCS for MCI.