Alzheimer's disease is characterized by progressive cognitive decline, and cognition is associated with cerebral concussion. Previous studies have found reduced gamma energy in the brain of AD patients. Therefore, modulation of gamma activity in AD patients may help improve cognitive function.

The purpose of this study was to investigate the safety and tolerability of transcranial alternating current stimulation (tACS) combined with 40Hz sound stimulation in patients with mild to moderate Alzheimer's disease (AD); to compare the effects of tACS combined with sound stimulation, tACS, and 40Hz sound stimulation on cognition in AD patients; and the effects of tACS combined with sound stimulation, tACS, and 40Hz sound stimulation on brain network connectivity in AD patients before and after tACS.

The number of people with Alzheimer's disease is increasing every year, but the available drugs are not effective. Both transcranial alternating current stimulation (tACS) and sound stimulation are non-invasive methods to modulate Central Nervous System excitability. tACS has been shown to modulate cognitive processes by affecting intrinsic oscillatory manipulation and entrainment in the brain. And 40 Hz sound stimulation reduces Aβ amyloid deposition in the hippocampus of AD mice.

Sixty patients with mild-to-moderate AD will be recruited in this randomized, double-blind, controlled study. The researchers will evaluate whether tACS (40Hz) to the DLPFC region or 40Hz sound stimulation to both ears improves cognition in patients with mild to moderate AD. The study will also investigate which stimulation method has a more pronounced and sustained improvement in cognition in the following three groups of patients.

Subjects will be randomized into three groups, with the first group receiving tACS combined with sound stimulation, the second group receiving tACS alone, and the third group receiving sound stimulation alone. All will receive three weeks (15 sessions) of treatment. Patients will be assessed by neuropsychological testing at baseline, post-treatment (21 days) and at the 3-month follow-up. Subjects will be compared by functional MRI at baseline and post-treatment for brain network connectivity before and after treatment.

Inclusion Criteria:

1. Age 40-80 years, male or female;
2. Meet the diagnosis AD formulated by the National Institute on Aging and the Alzheimer's Association (NIA-AA) dementia diagnostic criteria;
3. Clinical Dementia Rating Scale (CDR) =1.0 or 2.0;
4. MMSE score ≤ 24;
5. Able to move freely or with the aid of a walker or crutches;
6. Good vision and hearing, able to cooperate with examination and treatment;
7. Subjects voluntarily joined and had a guardian to sign the informed consent.

Exclusion Criteria:

1. The presence of preoperative structural brain abnormalities (such as tumors, cerebral infarction, hydrocephalus or intracranial hemorrhage);
2. The presence of other neurological disorders such as multiple sclerosis, epilepsy, Parkinson's disease, etc;
3. Psychiatric system disorders: such as anxiety disorders, affective disorders such as depression, or pharmacogenic psychiatric disorders;
4. Severe medical illness, current use of respiratory medications, cardiovascular medications, anticonvulsants or psychoactive drugs and clinically significant gastrointestinal, renal, hepatic, respiratory, infectious, endocrine or cardiovascular disease, cancer, alcoholism or drug addiction;
5. Severe hearing and visual impairment;
6. Patients with clinical comorbidities with a life expectancy of less than 2 years;
7. Patients who have undergone cranial surgery;
8. Contraindications to undergoing magnetic resonance imaging or receiving transcranial alternating current stimulation (pacemakers, post DBS surgery);
9. Eczema or sensitive skin;
10. Familial Alzheimer's disease;
11. Presence of other types of dementia: vascular dementia, Lewy body dementia, frontotemporal dementia, infectious dementia, etc;
12. Other conditions that, in the opinion of the investigator, may not be suitable for this study.