Background: Sleep disturbances, as a common symptom, can jeopardize the brain health and cognitive function and even lead to cognitive impairments in older adults. The co-occurring sleep disturbances cognitive complaints can significantly affect brain functions, and even be implicated as a key contributing factor in the development of prodromal Alzheimer's disease (AD). At present, very few non-pharmacological therapies are developed for managing these comorbidities in older adults. Focused low-intensity transcranial ultrasound stimulation (TUS) enables to stimulation the deep brain structures, such as hippocampus, with optimized focality and specific frequency.

Objectives: 1) To investigate the safety, feasibility and efficacy of a 2-week focused low-intensity hippocampal TUS on the severity of sleep disturbances and cognitive impairments in elderly patients; 2) to determine the sample size of a full-scale randomized clinical trial of low-intensity TUS in patients with preclinical AD; 3) to evaluate the effects of low-intensity TUS on the severity of sleep quality and cognitive functions at 2, 6 and 10 weeks after the treatments.

Design: A 2-week randomized, double-blind, controlled clinical trial. Methods: Chinese right-handed preclinical AD patients with sleep disturbances (aged from 60 to 90 years) will be randomly assigned to a 2-week intervention of either low intensity TUS or sham TUS, with 10 participants per arm. Before intervention, T1-weighted magnetic resonance imaging (MRI) data is used to construct individual realistic head model. Comprehensive assessments, including sleep quality, cognitive performance and plasma p-tau217, Aß42 and Aß40 will be conducted at baseline, 2nd week, 6th week and 10th week. Program adherence and adverse effects will be monitored throughout intervention.

Significance: This study aims to investigate the feasibility, safety and efficacy of low intensity hippocampal TUS for sleep disturbances and cognitive impairments in patients with preclinical Alzheimer's disease. It wills also test the program adherence, tolerability and adverse effects of this innovative neuromodulation. Information will be helpful for in-depth understanding the relationship of "sleep, glymphatic function and cognition" and guiding the further studies of neurodegenerative diseases and sleep medicine.

Data analysis: The primary outcomes will be the changes in sleep quality and cognition, and the comparisons of group differences across different time points. Secondary outcomes will be the changes of glymphatic function and neuropathological factors. Intention-to-treat analysis will be carried out. Changes of efficacy indicators from baseline to each follow up point will be tested with mixed effect model.

Inclusion Criteria:

• Chinese, right-handed, aged from 60 to 85 years.
• Mild neurocognitive disorder due to Alzheimer's disease (NCD-AD) is identified with the Montreal Cognitive Assessment (MoCA) score range from 22 to 26.
• Sleep disturbances or poor sleep quality is assessed and defined with a total score of the Pittsburgh Sleep Quality Index (PSQI) greater than 5.
• No impairments in the activities of daily living.

Exclusion Criteria:

• Previous diagnosis of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson disease.
• History of neurological diseases including brain tumor, and stroke.
• History of psychiatric disorders including schizophrenia and depression.
• Presence of positive neurological diseases, such as stroke, brain tumor, dementia.
• Physically unable to attend the sessions of intervention.
• Currently enrolled in another intervention study.
• Currently taking a psychiatric or other medication that may affect sleep quality and cognition.

This clinical trial will have patients' information.