This study aims to evaluate the safety and preliminary efficacy of combined auditory and visual 40-Hz stimulation in participants with biomarker-confirmed Alzheimer's disease spectrum disorders. A total of 60 participants with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia will be randomly assigned in a 1:1 ratio to receive either active multisensory 40-Hz stimulation or sham stimulation. The intervention will be administered for 60 minutes once daily for 4 consecutive weeks. Clinical assessments, electroencephalography, multimodal magnetic resonance imaging, and blood biomarkers will be evaluated before and after the intervention. Additional clinical, electroencephalographic, and blood biomarker assessments will be performed at 3 and 6 months after the intervention.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
60
A device delivering synchronized auditory and visual stimulation at a frequency of 40 Hz. Each intervention session will last 60 minutes and will be administered once daily for 4 consecutive weeks.
The sham device will reproduce the appearance, setup, and duration of the active intervention but will not deliver synchronized 40-Hz auditory and visual stimulation.
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale Score
The Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item version assesses cognitive performance in domains including memory, language, and praxis. Total scores range from 0 to 70, with higher scores indicating greater cognitive impairment. Change from baseline will be calculated as the post-intervention score minus the baseline score.
Time frame: Baseline to 1 week after completion of the 4-week intervention
Incidence of Treatment-Emergent Adverse Events
Number and proportion of participants experiencing one or more treatment-emergent adverse events from the first intervention session through completion of follow-up. Adverse events will be graded according to the Common Terminology Criteria for Adverse Events, version 5.0.
Time frame: From the first intervention session through 6 months after completion of the intervention
Change From Baseline in Resting-State Electroencephalographic Gamma-Band Power
Change in resting-state electroencephalographic power within the predefined gamma-frequency band following the intervention. Gamma-band power will be calculated using a prespecified electroencephalographic preprocessing and spectral analysis pipeline.
Time frame: Baseline to 1 week after completion of the 4-week intervention
Change From Baseline in Montreal Cognitive Assessment Score
The Montreal Cognitive Assessment evaluates global cognitive function. Total scores range from 0 to 30, with higher scores indicating better cognitive performance.
Time frame: Baseline to 1 week after completion of the 4-week intervention
Change From Baseline in Plasma Phosphorylated Tau 217 Concentration
Plasma phosphorylated tau 217 concentration will be measured in fasting blood samples using a prespecified validated assay.
Time frame: Baseline to 1 week after completion of the 4-week intervention
Glymphatic MRI marker
The DTI-ALPS index will be calculated from diffusion magnetic resonance imaging as a noninvasive imaging marker related to water diffusivity along perivascular spaces.
Time frame: Baseline to 1 week after completion of the 4-week intervention
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