Background: Little research exists on how individual risk factors for Alzheimer’s disease (AD) affect the intermediate phenotype after transcranial direct current stimulation (tDCS), despite the importance of precision medicine-based therapeutic approaches.

Objective: To determine how an application of sequential tDCS (2 mA/day, left dorsolateral prefrontal cortex, 10 sessions) affects changes in white matter (WM) microstructure integrity in 63 mild cognitive impairment (MCI) patients with effect modifiers such as Aβ deposition, APOE ε4 carrier status, BDNF Val66Met polymorphism status, and sex.

Methods: We examined individual effect modifier-by-tDCS interactions and multiple effect modifiers-by-tDCS interactions for diffusion metrics. We also evaluated the association between baseline Aβ deposition and changes in WM microstructure integrity following tDCS.

Results: We found that APOE ε4 carrier status and sex had a significant interaction with tDCS, resulting in increased fractional anisotropy (FA) in the right uncinate fasciculus (UF) after stimulation. Additionally, we observed multiple effect modifiers-by-tDCS interactions on WM integrity of the right UF, leading to a more pronounced increase in FA values in APOE ε4 carriers and females with Val66 homozygotes. Finally, baseline Aβ deposition was positively associated with a difference in FA of the left cingulum in the hippocampal area, which showed a positive association with the changes in the score for delayed memory.

Conclusion: Our study shows the differential impact of individual AD risk factors on changes in the early intermediate phenotype after sequential tDCS in MCI patients. This research emphasizes the importance of precision medicine approaches in tDCS for the prodromal stages of AD.