Temporal-Targeted Accelerated 40 Hz tACS Enhances Cognitive Function and Network Integration in Alzheimer's Disease: A Randomized Clinical Trial.

The temporal lobes are key hubs for memory and cognition. Although 40 Hz transcranial alternating current stimulation (tACS) has shown potential cognitive benefits, evidence for accelerated bilateral temporal stimulation remains limited. This study aims to evaluate its cognitive and neural effects. In this randomized, double-blind, controlled trial, 100 Alzheimer's disease (AD) patients were randomized 1:1 to active or sham 40 Hz tACS over the bilateral temporal. Cognitive outcomes at three time points were analyzed using mixed repeated-measures analysis of variance (ANOVA). Resting-state functional near-infrared spectroscopy (fNIRS) data from baseline and Week 4 were analyzed using ANOVA, followed by network-based statistics with family-wise error (FWE) correction. Eighty-five participants completed the trial. Significant Group × Time interactions were observed for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) total (p = 0.010), memory (p = 0.007), and praxis (p = 0.002), but not for the Mini-Mental State Examination (MMSE) (p = 0.075). The fNIRS analysis revealed a functional network primarily involving the frontal and parietal regions, comprising 38 connections and 18 nodes (pFWE = 0.010). Active-group connectivity changes were associated with ADAS-Cog total, language, praxis, and MMSE variations, but not in the sham group. Accelerated bilateral temporal 40 Hz tACS improved cognition and modulated frontotemporoparietal connectivity. Larger multicenter studies with biomarkers are warranted.