Miao Fang, Yibing Yan, Wenqian Song, Zhi Geng, Lu Wang, Chenyang Hu, Weiwei Li, Bing Song, Mengdan Chen, Yulong Dai, Yifan Hu, Shanshan Zhou, Haihua Guo, Gongjun Ji, Panpan Hu, Kai Wang, Xingqi Wu
BACKGROUND: Alzheimer’s disease (AD) is characterized by cognitive decline. Gamma-frequency (40 Hz) transcranial alternating current stimulation (tACS) may enhance cognition, although its efficacy and neural mechanisms remain unclear. This study evaluated whether 40-Hz tACS improves cognition in individuals with AD and explored the associated neural correlates using resting-state electroencephalography (rs-EEG) and plasma phosphorylated tau. METHODS: In a randomized, double-blind, sham-controlled trial, 39 participants with AD received either 40-Hz tACS (n = 20) or sham stimulation (n = 19) targeting the left dorsolateral prefrontal cortex (2.0 mA, 30 min/day, 2 weeks). Cognitive and mood outcomes and rs-EEG spectral and connectivity measures were assessed. RESULTS: Compared with sham, 40-Hz tACS was associated with a trajectory-level signal favoring improved global cognition, reduced depressive symptoms, increased frontal–central theta power, enhanced theta band hippocampal–prefrontal connectivity, stronger low-gamma connectivity at the ROI level, and exploratory reductions in plasma p-tau217 and p-tau181. CONCLUSION: Two weeks of low-intensity 40-Hz tACS showed target engagement and a trajectory-level cognitive signal in patients with AD. Biomarker changes were exploratory and require confirmation. TRIAL REGISTRATION: ClinicalTrials.gov NCT06565143 Date: 2024.08.19.