• Change in Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog, 11-items version). [ Time Frame: 3 months ]
  ADAS-cog 11 scale ranges from 0 to 70, and higher value represents a worse outcome. This study will use ADAS-cog to assess changes in the global cognitive function after intervention.
• Change in brain volume and white matter integrity [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Structural MRI will be used to measure brain volume and white matter integrity.
• Change in brain connectivity [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Functional MRI and resting-state EEG will be used to measure brain connectivity.
• Change in amyloid deposit in brain [ Time Frame: up to 21 days (end of intervention) ]
  PiB-PET will be used to analyze the amyloid deposit in brain.
• Change in Mini-mental State Examination [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Mini-mental State Examination (MMSE) will be used to evaluate the general cognitive function. MMSE ranges from 0 to 30, and higher value represents a better outcome.
• Change in Montreal Cognitive Assessment [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Montreal Cognitive Assessment (MoCA) will be used to evaluate the general cognitive function. MoCA ranges from 0 to 30, and higher value represents a better outcome.
• Change in Clinical Dementia Rating Scale sum of the boxes [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Clinical Dementia Rating Scale sum of the boxes (CDR-SB) will be used to evaluate the general cognitive function. CDR-SB ranges from 0 to 18, and higher value represents a worse outcome.
• Change in memory function [ Time Frame: up to 21 days (end of intervention), 3 months ]
  WHO-UCLA Auditory Verbal Learning Test will be used to assess memory function. It ranges from 0 to 45, and higher value represents a better outcome.
• Change in Digit span forward [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Digit span will be used to assess attention. It ranges from 3 to 10, and higher value represents a better outcome.
• Change in Digit span backward [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Digit span backward will be used to assess executive function. It ranges from 2 to 8, and higher value represents a better outcome.
• Change in Trail Making Test [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Trail-Making Test B minus A score will be used to assess executive function. Trail-Making Test B minus A ranges from -150 to 300, higher value represents a worse outcome.
• Change in Boston Naming Test [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Boston Naming Test will be used to assess language function. It ranges from 0 to 30, and higher value represents a better outcome.
• Change in Neuropsychiatric Inventory (NPI) [ Time Frame: up to 21 days (end of intervention), 3 months ]
  The Neuropsychiatric Inventory will be used to measure neuropsychiatric symptoms. It ranges from 0 to 144, and higher value represents a worse outcome.
• Change in Geriatric Depression Scale (GDS) [ Time Frame: up to 21 days (end of intervention), 3 months ]
  The Geriatric Depression Scale will be used to measure neuropsychiatric symptoms. It ranges from 0 to 30, and higher value represents a worse outcome.
• Change in Activities of Daily Living [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Activities of Daily Living (ADL) scale will be used to assess the change of life quality. It ranges from 20 to 80. The "20" represents normal life ability and the higher score presents the worse life ability.
• Side-effects of tACS [ Time Frame: up to 21 days (end of intervention), 3 months ]
  Adverse Events as a result of tACS stimulation will be reported.

• Change in Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog, 13-items version). [ Time Frame: 6 months ]
  ADAS-cog 13 scale ranges from 0 to 80, and higher value represents a worse outcome. This study will use ADAS-cog to assess changes in the global cognitive function after intervention.
• Change in brain volume and white matter integrity [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Structural MRI (including DTI) will be used to measure brain volume and white matter integrity.
• Change in brain connectivity [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Functional MRI and resting-state EEG will be used to measure brain connectivity.
• Change in amyloid deposit in brain [ Time Frame: up to 80 days (end of intervention), 6 months ]
  PiB-PET will be used to analyze the amyloid deposit in brain.
• Change in Mini-mental State Examination [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Mini-mental State Examination (MMSE) will be used to evaluate the general cognitive function. MMSE ranges from 0 to 30, and higher value represents a better outcome.
• Change in Montreal Cognitive Assessment [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Montreal Cognitive Assessment (MoCA) will be used to evaluate the general cognitive function. MoCA ranges from 0 to 30, and higher value represents a better outcome.
• Change in Clinical Dementia Rating Scale sum of the boxes [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Clinical Dementia Rating Scale sum of the boxes (CDR-SB) will be used to evaluate the general cognitive function. CDR-SB ranges from 0 to 18, and higher value represents a worse outcome.
• Change in memory function [ Time Frame: up to 80 days (end of intervention), 6 months ]
  WHO-UCLA Auditory Verbal Learning Test will be used to assess memory function. It ranges from 0 to 45, and higher value represents a better outcome.
• Change in Digit span forward [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Digit span will be used to assess attention. It ranges from 3 to 10, and higher value represents a better outcome.
• Change in Digit span backward [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Digit span backward will be used to assess executive function. It ranges from 2 to 8, and higher value represents a better outcome.
• Change in Trail Making Test [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Trail-Making Test B minus A score will be used to assess executive function. Trail-Making Test B minus A ranges from -150 to 300, higher value represents a worse outcome.
• Change in Boston Naming Test [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Boston Naming Test will be used to assess language function. It ranges from 0 to 30, and higher value represents a better outcome.
• Change in Neuropsychiatric Inventory (NPI) [ Time Frame: up to 80 days (end of intervention), 6 months ]
  The Neuropsychiatric Inventory will be used to measure neuropsychiatric symptoms. It ranges from 0 to 144, and higher value represents a worse outcome.
• Change in Geriatric Depression Scale (GDS) [ Time Frame: up to 80 days (end of intervention), 6 months ]
  The Geriatric Depression Scale will be used to measure neuropsychiatric symptoms. It ranges from 0 to 30, and higher value represents a worse outcome.
• Change in Activities of Daily Living [ Time Frame: up to 80 days (end of intervention), 6 months ]
  Activities of Daily Living (ADL) scale will be used to assess the change of life quality. It ranges from 20 to 80. The "20" represents normal life ability and the higher score presents the worse life ability.

Background: Alzheimer's disease (AD) is the most prevalent cause of dementia. Given the limited efficacy of pharmacological treatments, non-pharmacological approaches in AD are of great interest. In these approaches, brain stimulation technique is an important one, because of its potential to modulate cognitive functions in many neuropsychiatric diseases. Transcranial alternating current stimulation (tACS), as a neuromodulatory technique, oscillates a sinusoidal current at a chosen frequency to interact with the brain's natural cortical oscillations. Hypothetically, tACS would reduce cortical hyperactivity and induces cognitive improvement or delay cognitive decline in patients with AD.

Objectives This double-blinded, randomized controlled trial evaluates the efficacy and safety of tACS in patients with mild AD. The second objective is to evaluate the effect of tACS on neural plasticity, which is assessed by structural and functional MRI, PiB-PET, and resting-state EEG.

Patients and Methods The proposed study is a double-blinded, randomized controlled trial that will include 40 individuals with mild AD with positive findings in amyloid PET imaging or amyloid protein levels in CSF. The participants will be randomized to either a tACS group or a sham stimulation group. Both groups will undergo 30 one-hour sessions in 3 weeks (21 days). All the outcomes will be assessed at baseline, end of intervention and 3 months after the first intervention to measure long-term resilience of the effect.

• Device: transcranial alternating current stimulation
  The alternating current is administered through medical grade conductive pads that are produced specifically for the Nexalin technology. The pads are places on the forehead and behind each ear, and are connected to the Nexalin device with thin cables. Intervention will be implemented with a tACS device with gamma-frequency (40 Hz) and a peak-to-peak amplitude of 15mA, 30 one-hour sessions in 3 weeks (21 days).
• Device: sham stimulation
  Electrodes will also be put on patient's forehead and behind each ear. The sham stimulator has the exactly same appearance with the true stimulator. Participants and operators cannot determine whether the stimulator is true based on its appearance or patients' feelings. However, when the device is started, no current flows through the electrodes. Participants in this controlled group will also receive sham stimulations with 30 one-hour sessions in 21 days.

• Experimental: tACS stimulation group
  NEXALIN ADI transcranial alternating current stimulator
  Intervention: Device: transcranial alternating current stimulation
• Sham Comparator: sham stimulation group
  Sham stimulator provided by NEXALIN company
  Intervention: Device: sham stimulation

Inclusion criteria

1. Subjects with informed consent;
2. 45-75 years of age;
3. At least 6 years of education;
4. AD according to the National Institute on Aging and the Alzheimer's Association (NIA-AA) guidelines;
5. Clinical Dementia Rating Scale (CDR)=1.0;
6. Positive findings in amyloid PET imaging or decreased CSF levels of Aβ1-42;
7. On a stable dose of cholinesterase inhibitors (e.g. donepezil or rivastigmine) as defined as 6 consecutive weeks of treatment at an unchanging dose, and without any intentions to modify the dosage during the observation period.

Exclusion criteria

1. Current or past history of any neurological disorder other than dementia, such as epilepsy, stroke, progressive neurologic disease (e.g. multiple sclerosis), poorly controlled migraines or intracranial brain lesions; and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment;
2. Contraindication for undergoing MRI or receiving tACS;
3. Eczema or sensitive skin;
4. Familial AD;
5. Depression or other psychiatric disorders;
6. Abnormal brain structural magnetic resonance imaging (MRI) scan, including hydrocephalus, stroke, structural lesions, etc. that would potentially confound the outcome;
7. Severe cardiovascular/pulmonary disorders;
8. Other conditions, in the investigator's opinion, might not be suitable for the study.