Effects of 40 Hz Transcranial Alternating Current Stimulation on Cognitive Changes and Neural Markers in Alzheimer's Disease: A Randomized, Double Blind, Sham Controlled Trial

Alzheimer's disease (AD) is a neurodegenerative disorder characterized primarily by progressive cognitive decline and impaired daily functioning, representing a major public health challenge in aging societies. Although disease modifying therapies have advanced in recent years, their high costs, administration routes, and limited accessibility underscore the need for repeatable, non invasive intervention strategies suitable for long term management.

Gamma band neural oscillations play a critical role in cognitive processing and cross regional information integration, and patients with AD frequently exhibit aberrant gamma activity. Previous preclinical studies have suggested that 40 Hz sensory or electrical stimulation may ameliorate oscillatory abnormalities and influence Aβ  and tau related pathological processes. However, randomized controlled evidence examining the effects of 40 Hz transcranial alternating current stimulation (tACS) on cognitive outcomes, EEG networks, and fluid biomarkers in clinical populations remains limited.

Recently, Professor Kai Wang's team from the Department of Neurology at the First Affiliated Hospital of Anhui Medical University published an article titled "Effects of 40Hz transcranial alternating current stimulation on cognition and neural markers in Alzheimer's disease: a randomized, sham controlled trial" in Alzheimer's Research & Therapy (IF: 7.6, CAS Q1). The study's co first authors are graduate student Miao Fang, Dr. Yibing Yan, and graduate student Wenqian Song from the Department of Neurology at the First Affiliated Hospital of Anhui Medical University, with Professors Xingqi Wu, Panpan Hu, and Kai Wang serving as co corresponding authors.[1]

Based on a randomized, double blind, sham controlled clinical trial (NCT06565143), the study enrolled 40 patients with AD and evaluated the effects of 2.0 mA, 40 Hz tACS targeting the left dorsolateral prefrontal cortex (DLPFC) delivered for 14 consecutive days (30 minutes daily) on cognition, mood, resting state EEG, and plasma biomarkers. The results showed that although 40 Hz tACS did not yield significant between group differences in absolute ADAS Cog scores at cross sectional time points, it demonstrated potential beneficial signals at the level of cognitive trajectory. Additionally, the active stimulation group exhibited increased frontal central theta power, enhanced 

prefrontal hippocampal theta connectivity, strengthened low gamma (30- 50 Hz) functional connectivity, and exploratory reductions in plasma p tau217 and p tau181. Further mediation analysis suggested that the reduction in p tau181 may partially mediate cognitive improvement. Overall, this study provides new clinical evidence supporting 40 Hz tACS as an intervention for AD across multiple dimensions, including neural oscillations, brain network connectivity, and peripheral molecular markers.

I. Study Design and Procedures

Following screening and randomization, 39 patients completed the post treatment assessment. No significant differences in baseline demographic or clinical characteristics were observed between the two groups. Participants underwent cognitive scale assessments, EEG recordings, and plasma sample collection at baseline and within 48 hours after treatment completion, with a further cognitive follow up at 3 months.

II. Cognitive and Mood Outcomes

Linear mixed effects model analysis revealed a significant group by time interaction effect on the primary cognitive outcome, the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS Cog), indicating differences in cognitive trajectories between the active and sham groups. However, no significant between group differences were observed at the end of treatment or at the 3 month follow up when comparing single time points. Overall, the effects of 40 Hz tACS were more evident as potential benefits at the trajectory level rather than as cross sectional between group superiority. Meanwhile, the Montreal Cognitive Assessment (MoCA) showed an improving trend in the active group at both post treatment and follow up, and the Hamilton Depression Rating Scale (HAMD) also showed some improvement post treatment, while no clear between group differences were observed in other cognitive and behavioral scales.

III. Resting State EEG Spectral Power and Functional Connectivity

Resting state EEG analysis revealed increased theta band power in the active stimulation group after treatment, with statistical significance in certain brain regions after multiple comparisons correction. Functional connectivity analysis further indicated enhanced low gamma band connectivity in the active group, primarily involving frontotemporal and frontoparietal/central pathways; source localization also revealed enhanced prefrontal hippocampal theta functional connectivity. These findings suggest that 40 Hz tACS may participate in cognitive regulation through modulation of local neural oscillations and long range network connectivity.

IV. Changes in Plasma Phosphorylated Tau and Mediation Analysis

In exploratory subsample analyses, the 40 Hz tACS group showed reductions in both plasma p tau217 and p tau181 levels, suggesting that the intervention may influence tau related molecular processes in addition to modulating neural electrical activity. Further mediation analysis suggested that the reduction in p tau181 may partially mediate cognitive improvement; however, given the exploratory nature of this analysis, the mechanistic implications require confirmation in larger samples.

V. Safety and Tolerability

All adverse events were mild and transient (e.g., local tingling, itching), with no serious adverse events reported, supporting the feasibility and safety of 2.0 mA 40 Hz tACS in outpatient AD populations.

Overall, this study systematically evaluated the multimodal effects of low intensity 40 Hz tACS in AD across cognitive outcomes, EEG oscillations and functional connectivity, and plasma tau biomarkers. Although ADAS Cog did not show significant between group differences at any single time point, the cognitive trajectory signals, EEG changes, and plasma p tau reductions collectively suggest that this intervention protocol may hold potential clinical value.

The study remains limited by sample size and validation approaches in some electrophysiological and biomarker analyses, and the mediation results should be interpreted with caution. Future multi center studies with longer follow up, combined with dose optimization and causal modeling, are needed to further elucidate the optimal parameters and mechanisms of tACS intervention in AD.

[1] Miao Fang, Yibing Yan, Wenqian Song, et al. Effects of 40-Hz transcranial alternating current stimulation on cognition and neural markers in Alzheimer's disease: a randomized, sham-controlled trial. PubMed. 10.1186/s13195-026-02033-4.
https://pubmed.ncbi.nlm.nih.gov/41918026