Effects of 40-Hz transcranial alternating current stimulation on cognition and neural markers in Alzheimer’s disease: a randomized, sham-controlled trial

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.