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Effects of 40 Hz transcranial alternating current stimulation (tACS) on cognitive functions of patients with Alzheimer’s disease: a randomised, double-blind, sham-controlled clinical trial
  1. Dongsheng Zhou1,
  2. Ang Li2,3,4,5,
  3. Xingxing Li1,
  4. Wenhao Zhuang1,
  5. Yiyao Liang2,
  6. Cheng-Ying Zheng1,
  7. Hong Zheng1,
  8. Ti-Fei Yuan6,7,8
  1. 1 Ningbo Kangning Hospital, Ningbo, Zhejiang, People's Republic of China
  2. 2 Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong, People's Republic of China
  3. 3 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, People's Republic of China
  4. 4 Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou, Guangdong, People's Republic of China
  5. 5 Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China
  6. 6 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
  7. 7 Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, People's Republic of China
  8. 8 Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, People's Republic of China
  1. Correspondence to Dr Ti-Fei Yuan, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, People's Republic of China; ytf0707{at}

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Gamma frequency stimulation is found to alleviate memory deficits on animal models of Alzheimer’s disease (AD), potentially by activating neuroimmune signalling and removing A-beta plaques in the brain.1 2 A feasible, translational hypothesis is that gamma band brain stimulation (eg, transcranial alternating current stimulation (tACS)) would yield clinical benefits on cognition in patients with AD. Here we performed a 6-week gamma tACS (2 mA, 40 Hz over bilateral temporal lobes) on a total of 50 subjects to elucidate clinical efficiency and safety of gamma stimulation for patients with AD.


The study included a 6-week tACS intervention phase (5 days on and 2 days off for weekends) and another 12-week efficacy/safety assessment phase without tACS intervention (figure 1A). Bilateral tACS over temporal lobes (located by 10–20 electroencephalogram system) was delivered through saline-soaked sponges (sized 4×4 cm2) using a stimulator (Transcranial, London, UK). The 40 Hz sinusoidal current was applied at 2 mA with a duration of 20 min. Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Cognitive Component Assessment (ADAS-Cog) were used for cognition evaluation before (0 week), at the end of (6 weeks) and 12 weeks (end +12 weeks) after the end of the stimulation. Serum A-beta levels were measured with ELISA.

Figure 1

Effects of tACS on cognitive functions and serum Aβ levels in patients with AD. (A) Consolidated Standards of Reporting Trials diagram of the primary phases of the clinical trial. (B,C) MMSE score (B) and ADAS-Cog total score (C) at the designated time points. There was no significant difference between tACS group and sham group at baseline for either MMSE (F=0.60, p=0.44) or ADAS-Cog total score (F=0.09, p=0.77). Repeated measures analysis of variance revealed a significant time effect (MMSE: F(2,48)=33.91, p<0.01; ADAS-Cog: F(2,48)=10.84, p<0.01) and an interaction effect (time×group) (MMSE: F(2,48)=5.92, p<0.01; ADAS-Cog: F(2,48)=6.43, p=0.002), but not a group …

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  • DZ, AL, XL and WZ contributed equally.

  • Contributors DZ and TY designed the study; DZ, AL, XL, WZ, YL, C-YZ and HZ performed the experiments; DZ, AL, XL, WZ and TY analysed the results and wrote the paper. All authors read and approved the final version of the manuscript.

  • Funding Supported by grants from the Basic Public Welfare Project of Zhejiang Province (LGF21H090008), Ningbo Natural Science Foundation (2019A610297) to DZ; Natural Science Foundation of Zhejiang Province (LQ21H170001), Zhejiang Medical and Health Science and Technology programme (2020KY285 and 2020KY286) to XL and WZ; Science and Technology Commission of Shanghai Municipality (18JC1420304) to TFY; NSFC (82071372), Guangdong Key Laboratory of Non-human Primate Research (2020B121201006), Outstanding Scholar Program of Bioland Laboratory (2018GZR110102002), Science and Technology Program of Guangzhou (202007030012) to AL.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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