Alzheimer's Disease (AD) is the primary cause of dementia, with its prominent feature being cognitive decline. The cerebellum plays a crucial role in cognitive processing, making it a potential target for therapeutic intervention. This study will be conducted to evaluate the efficacy and safety of cerebellar Intermittent theta-burst stimulation (CRB-iTBS) in participants with mild Alzheimer's disease on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 3 months of treatment in the Core Study. This project aims to provide a valid treatment to improve the cognitive function and quality of life for those with Alzheimer's disease.

Background:

Alzheimer's disease (AD) is a progressive neurodegenerative disease that poses substantial challenges for both families and society. The primary pathological hallmarks of AD are β-amyloid plaque (Aβ) deposition and neurofibrillary tangles. Notably, the cerebellum seems to be resilient to these pathological developments in the initial phases of AD. This early resistance of the cerebellum suggests it might contribute to compensating for the cognitive impairments associated with AD. Enhancing cerebellar reserve is a potential therapeutic approach. Repetitive transcranial magnetic stimulation (rTMS) has been explored as a means to achieve this, attributed to synaptic plasticity in the cerebellar cortex.

Hypothesis:

The cerebellar dentate nucleus (CDN), a crucial node for information transmission between the cerebellum and cerebral cortex, shows abnormal functional connectivity with cortex in AD patients. Preclinical studies demonstrated that stimulating lateral cerebellar nucleus, the rodent homologue of the human CDN, enhanced cognitive rehabilitation and improved cortical plasticity in animals after brain injury, suggesting CDN as a neuromodulation target for cognitive networks. We speculate that intermittent θ-burst stimulation (iTBS) based TMS targeting the cerebellar dentate nucleus may improve cognitive function, brain function, and lymphatic drainage in AD patients.

Specific aims:

In this study, we will conduct a randomized, double-blind, sham-controlled clinical trial focusing on the cerebellum with iTBS to assess its efficacy, safety and potential mechanisms in the treatment of AD patients. The findings yielded by the present project will have a potential strong impact on clinical practice of AD patients. Since rTMS is well tolerated and relatively low-priced, a positive result could lead to a fast application of the present proposal to the clinical experience. If successful, the proposed project will provide support for a novel treatment for cognitive dysfunction in AD patients.

Inclusion Criteria:

1. Age: 50-85 years old
2. Meet the core clinical criteria of NIA-AA for possible Alzheimer's disease dementia, and PET or cerebrospinal fluid markers show elevated p-tau and decreased A β (1-42)
3. MMSE score ranges from 18-26 points; CDR score 0.5-1 points
4. The patient has received treatment with acetylcholinesterase inhibitors (AChEI), NMDA receptor antagonists, or mannequine therapy, and the current dosing regimen has remained stable for the 12 weeks prior to baseline assessment
5. At least one adult caregiver
6. The patient or legal guardian voluntarily signs the informed consent form

Exclusion Criteria:

1. Neurodegenerative disorders other than AD.

2. Significant intracranial focal or vascular pathology seen on brain MRI scan

3. History of seizure (with the exception of febrile seizures in childhood)

4. Any of the following psychotic disorders (DSM IV-TR criteria):

   • Major depressive disorder (current)
   • Schizophrenia
   • Other psychotic disorders, bipolar disorder, or substance related disorders (within the past 5 years)

5. GDS score ≥ 8 points in baseline assessment

6. Cerebrovascular disease, severe infection, malignant tumor, or severe dysfunction of organs such as heart, liver, and kidney.

7. Pregnant or lactating women

8. Contraindications for TMS or MRI, metal or implanted devices in the body (such as pacemakers, deep brain stimulators).

9. Participate in AD related clinical trials within 6 months prior to research registration