Abstract
Cognitive deficits are a hallmark of Alzheimer’s disease (AD), and effective treatments remain elusive. Transcranial alternating current stimulation (tACS), a non-invasive technique, has shown potential in improving cognitive function across various populations, but further research is needed to investigate its efficacy in AD. In a randomized, double-blind, sham-controlled pilot trial, 36 mild AD patients received active or sham theta-tACS (8 Hz, 1.6 mA, 20-min daily) during n-back task for two weeks, followed by a 10-week follow-up. Cognitive assessments and resting-state EEG were analyzed at baseline, after-treatment, and follow-up. The results showed that the active group demonstrated significant cognitive improvements after treatment (MMSE: t (15) =-3.273, p = 0.005, Cohen’s d = 0.82), particularly in short-term memory (MMSE-recall: Z = -2.11, p = 0.035, r = 0.53), with maintained benefits after 10 weeks. In contrast, the sham group exhibited long-term cognitive decline (MMSE: t (4) = 3.586, p = 0.023, Cohen’s d = -1.60). EEG analysis revealed reduced gamma power (t (23) = 2.689, p = 0.013, Cohen’s d = 1.077) and theta connectivity in active group, particularly in the frontotemporal regions (F4/F7: t (23) = 2.467, p = 0.021, Cohen’s d = 0.988; F4/T3: t (23) = 2.465, p = 0.022, Cohen’s d = 0.987), which was correlated with cognitive improvements (R = –0.57, p = 0.043). In conclusion, tACS combining cognitive training may offer cognitive benefits in mild AD by modulating neural activity, though further studies are needed to clarify its mechanisms.
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Data availability
The data that support the findings of this study are not publicly available due to privacy restrictions but are available from the corresponding author upon reasonable request.
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Acknowledgements
We acknowledge the patients and their families, clinical and administrative staff for their important contributions. We also appreciate Shenzhen Zhongkehuayi Technology Company for technical support.
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 82101581, 82071181, 82371453), the National Key R&D Program Strategic Science and Technology Innovation Cooperation key special project (SQ2023YFE0201430), STI2030-Major Projects (2022ZD0212400), Key R&D Program of Zhejiang (2024SSYS0017, 2024C03006, 2024C04024, 2025C01119), Fundamental Research Funds for the Central Universities (2025ZFJH01-01). This work was also funded by the Psych-STRATA project (European Union’s Horizon Europe programme, grant No. 101057454).
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Wei C. and Qian G. contributed equally to the conception and design of the study. Kehua Y., Dandan C., Xinhui L., Zhongmei Y., and Dandan L. were responsible for clinical patient management and administering the intervention (equal contribution). Qian G., Daxi F., Lili W., Chanchan S., Yingchun Z., Luoyi X., and Wenjuan C. collected patient data (equal contribution). Shuying R. and Haiteng J. processed and analyzed the EEG data. Xuemin F., Benno P., and Bertram M.-M. provided statistical support and data visualization (equal contribution). Qian G. and Xuemin F. interpreted the data and drafted the manuscript (equal contribution). Daxi F., Benno P., Bertram M.-M. and Pengfei Wei reviewed and made grammatical revisions to the manuscript (equal contribution). Wei C. and Haiteng J. critically revised and gave final approval of the manuscript (equal contribution). All authors read and approved of the final manuscript.
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Gong, Q., Fu, X., Feng, D. et al. Randomized, double-blind, sham-controlled pilot trial of theta-band transcranial alternating current stimulation during cognitive training in mild Alzheimer’s disease. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03822-z
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DOI: https://doi.org/10.1038/s41398-026-03822-z
