Overview

The goal of this clinical trial is to learn if personalized, multimodal imaging-guided, EEG-based closed-loop Temporal Interference Brain Stimulation (TIBS) can improve memory function in individuals with preclinical Alzheimer's Disease (AD).

The main questions it aims to answer are:

1. Does personalized TIBS lead to significant changes in functional connectivity strength of hippocampal-cortical networks at the end of the 2-week intervention compared to baseline?
2. What are the short-term (end of 2-week intervention) and medium-to-long-term (4 weeks and 12 weeks post-intervention) effects of personalized TIBS on episodic and working memory, as well as other cognitive domains in preclinical AD?
3. How does personalized TIBS modulate brain activity and connectivity, as measured by EEG power spectra and functional MRI (fMRI) functional connectivity, in preclinical AD?
4. What is the safety profile of personalized TIBS in this population?

Researchers will compare participants receiving active personalized TIBS to participants receiving sham (inactive) stimulation to see if TIBS effectively improves memory function and induces neural plasticity.

Participants will:

1. Undergo initial screening including neuropsychological assessments and blood p-tau217 testing to identify preclinical AD.
2. Receive either active personalized TIBS or sham stimulation daily for 40 minutes, 6 days a week, for 2 weeks.
3. Have individualized TIBS parameters (e.g., target localization, intensity) determined using baseline structural MRI and DTI.
4. Undergo real-time high-density EEG monitoring during daily stimulation sessions to enable closed-loop adjustment of stimulation parameters.
5. Participate in follow-up assessments at the end of the 2-week intervention, and at 4 weeks and 12 weeks post-intervention.
6. Receive multimodal imaging (sMRI, rs-fMRI, task-fMRI, DTI) and blood biomarker assessments at various time points.
7. Receive Aβ-PET and tau-PET scans, along with comprehensive neuropsychological assessments, at the 12-week follow-up.
8. Have their safety continuously monitored throughout the study.

Eligibility

Inclusion Criteria:

• Individuals recruited from neurology memory clinics or communities.
• Age between 60 and 80 years old, inclusive; no gender limitation.
• Right-handed.
• Cognitive function test results within normal range after age, gender, and education-level adjustment, OR mild cognitive impairment not yet meeting diagnostic criteria for Mild Cognitive Impairment (MCI), OR only subjective cognitive decline.
• Individuals classified as preclinical AD based on the revised 2024 AD diagnostic and staging criteria (i.e., cognitively normal with positive plasma p-tau217 or positive Aβ PET).
• Full understanding of the study, voluntary participation, and provision of written informed consent approved by the Ethics Committee.

Exclusion Criteria:

• Past or present neurological diseases (e.g., stroke, epilepsy, Parkinson's disease, multiple sclerosis).
• Psychiatric disorders such as severe depression or severe anxiety.
• Systemic diseases causing cognitive decline (e.g., severe thyroid dysfunction, severe liver or kidney disease, severe nutritional deficiencies).
• Currently taking medications that may affect cognitive function (e.g., anticholinergics, benzodiazepines, antipsychotics) that cannot be discontinued or adjusted.
• Other factors leading to cognitive decline that are not AD-related.
• Contraindications for MRI scans, such as claustrophobia, implanted metallic devices (e.g., pacemakers, cochlear implants, aneurysm clips), or history of head injury with retained metal fragments.