Transcranial Alternating Current Stimulation for Patients With Mild Alzheimer's Disease II (TRANSFORM-AD II)

Background In our previous study, we applied 40 Hz transcranial alternating current stimulation (tACS) to patients with mild Alzheimer's disease (AD), and the results demonstrated significant improvements in cognitive function. Building upon these findings, the present study applies a combined high-gamma (77.5 Hz) and low-gamma (40 Hz) tACS protocol to target patients with amnestic mild cognitive impairment due to Alzheimer's disease (AD-aMCI) and those with mild Alzheimer's disease dementia (AD-MD). This dual-frequency stimulation aims to enhance cognitive performance through synergistic gamma-band modulation and to explore its underlying therapeutic mechanisms. Methods The TRANSFORM-AD II trial is a double-blind, randomized controlled study that will enroll 160 participants diagnosed with AD-aMCI or AD-MD. Eligible participants must meet at least one of the following criteria: positive amyloid positron emission tomography (PET), decreased cerebrospinal fluid (CSF) amyloid-β levels, or elevated plasma phosphorylated tau 217 (p-Tau217) levels. Participants will be randomly assigned to either the active stimulation group (77.5 Hz + 40 Hz tACS) or the sham stimulation group. Both groups will receive 60 one-hour sessions over an 8-week period. Outcome measures will be assessed at baseline and immediately after the intervention. The primary outcome is global cognitive function, measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13). Secondary outcomes include changes in other neuropsychological test scores, multimodal magnetic resonance imaging (MRI) metrics, and resting-state as well as task-related electroencephalography (EEG) indicators. Results This trial is currently ongoing, with recruitment expected to be completed by June 2026. Conclusion This study will evaluate the efficacy and safety of combined 77.5 Hz and 40 Hz tACS in patients with AD-related aMCI and mild AD dementia. Furthermore, it will investigate potential therapeutic mechanisms using multimodal MRI to assess brain structure and function, and EEG to characterize both resting-state and task-related neural activity patterns.