Multisensory 40-Hz Stimulation for Alzheimer's Disease

Alzheimer's disease is associated with abnormalities in neural network activity and gamma-frequency oscillations. Preclinical studies suggest that sensory stimulation at 40 Hz may entrain gamma oscillations and influence Alzheimer's disease-related pathological and functional changes.

This single-center, prospective, randomized, sham-controlled study will investigate the safety and preliminary efficacy of combined auditory and visual 40-Hz stimulation in participants with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia. Eligible participants will have evidence of Alzheimer's disease pathology based on positron emission tomography, cerebrospinal fluid, or blood biomarkers.

Participants will be randomly assigned in a 1:1 ratio to active multisensory 40-Hz stimulation or sham stimulation. Both interventions will be administered for 60 minutes once daily for 4 weeks. Clinical assessments, electroencephalography, multimodal magnetic resonance imaging, and blood biomarkers will be obtained at baseline and after completion of the intervention. Clinical assessments, electroencephalography, and blood biomarkers will also be collected at 3 and 6 months after treatment to assess the durability of treatment effects. Safety will be evaluated through the incidence and severity of adverse events throughout the intervention and follow-up periods.

Inclusion criteria

• Provision of written informed consent by the participant or the participant's legally authorized representative.
• Age 45 to 75 years, inclusive.
• Completion of at least primary school education.
• Diagnosis within the Alzheimer's disease spectrum according to the National 5.Institute on Aging and Alzheimer's Association criteria.

Mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, defined by a Montreal Cognitive Assessment score of ≤24 for participants with middle school education or above, or ≤23 for participants with primary school education, and a Clinical Dementia Rating global score of 0.5 or 1.

6.Evidence of Alzheimer's disease pathology based on a positive positron emission tomography, cerebrospinal fluid, or blood biomarker result.

7.Alzheimer's disease-related medications are expected to remain stable during the study period.

Exclusion criteria

• Current or previous history of a neurological disorder other than Alzheimer's disease that may affect cognition or study assessments, including epilepsy, stroke, multiple sclerosis, poorly controlled migraine, intracranial injury, previous neurosurgery, or head trauma with residual neurological impairment.
• Contraindication to magnetic resonance imaging, electroencephalography, auditory stimulation, visual stimulation, or noninvasive brain stimulation.
• Current major depressive disorder or another psychiatric disorder that, in the investigator's judgment, may interfere with study participation or outcome assessment.
• Clinically significant structural abnormalities on brain magnetic resonance imaging, including hydrocephalus, stroke, or another structural lesion that may confound study results.
• Severe cardiovascular or pulmonary disease.
• Cognitive impairment primarily attributable to another disorder, including frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease dementia, or vascular dementia.
• Clinically significant suicide risk or a suicide attempt within the previous 12 months.
• Behavioral disturbance, including severe aggression, agitation, or impulsivity, that may interfere with adherence to study procedures.
• Current or planned treatment with an anti-amyloid monoclonal antibody during the study period.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.