Large-coil Parietal Repetitive Transcranial Magnetic Stimulation (rTMS) for Alzheimer Disease (AD)

The goal of this clinical trial is to learn if using large-coil (or "deep") repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus and surrounding areas is feasible, tolerable, and potentially efficacious for memory in Alzheimer's Disease. Previous work studying rTMS in Alzheimer's is mixed, but recent work studying rTMS of the precuneus is encouraging for both its short-term and long-term effects. The main questions this study aims to answer are:

• Is deep rTMS of the precuneus feasible and tolerable in Alzheimer's?
• Are there signs of positive brain changes in response to deep rTMS?
• Is deep rTMS potentially efficacious for memory in Alzheimer's? Researchers will compare active stimulation to placebo stimulation while obtaining memory testing and measurements of the brain (imaging, scalp electrode measurements, bloodwork) to see if active treatment works to treat Mild Cognitive Impairment (MCI) and mild-to-moderate dementia due to Alzheimer's disease.

Participants will:

• Engage with memory testing, brain scans, and bloodwork during a comprehensive assessment
• Visit the clinic 3 times for 12 consolidated rTMS sessions, followed by 8 once weekly maintenance visits
• Be offered a full open-label active treatment course after completing their treatment course if they are initially in the placebo group

This study is designed to examine whether non-invasive electromagnetic stimulation of a specific brain region can help improve memory in the short-term in Alzheimer's Disease (AD). AD is a progressive neurodegenerative disease that affects multiple domains, including cognitive (e.g. memory, executive function), behavioral (e.g. wandering, difficulty controlling impulses, irritability), emotional (e.g. anxiety, depression), and functional (e.g. ability to live independently and complete activities of daily living) domains. It is also associated with increased caregiver burden, which can adversely affect caregivers' health.

One increasingly apparent contributor to disease progression in AD is brain network dysregulation, particularly within the default mode network. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive therapeutic modality that can be used to stimulate the precuneus, a key node in the default mode network, and maintain signaling function within the default mode network. Previous studies have shown that targeting the precuneus with rTMS may enhance memory in the short term and delay disease progression and functional decline in AD over longer periods. rTMS protocols that have demonstrated promise for treatment delay have first shown short-term impacts on memory, particularly memory of recent and past events.

We will conduct a two-stage trial of rTMS targeting the precuneus in patients with mild to moderate probable AD focused primarily on determining safety and feasibility and secondarily focused on determining short-term efficacy for memory. Participants will be recruited through fliers, social media, print, and web advertising, as well as referrals from other UCLA studies, UCLA clinics, and known community clinics. The first stage (completed May 2026) consisted of a handful of participants (n=10) with mild-moderate Alzheimer's Clinical Syndrome receiving active treatment only to refine the protocol. As expected, this stage of the study has led to refinements, including extending the duration of the randomized trial stage from 5 weeks to 9 weeks and intensifying the maintenance treatment.

The second stage of the trial will consist of a randomized, double-blind, sham controlled clinical trial with open-label extension (for the sham group after completion and breaking blind) examining both safety and short-term efficacy for memory. Participants will be randomized on a 1:1 ratio to either receive precuneus or sham rTMS. The primary outcome is completion rate, and the study is designed primarily to assess feasibility and tolerability.

Participants will undergo 28 total rTMS brain stimulation sessions (each session being about 20 minutes) over the course of 9 weeks. The initial induction 3-day intensive course in which rTMS (or sham) will be applied four times daily with 30-60 minute breaks between treatments will be followed by an 8-week maintenance course in which stimulation will be applied in once weekly visits (two stimulation sessions each visit with a brief break in-between).

Participants will undergo a range of assessments including brain imaging and oxygenation, genotyping and blood biomarker assessment, and brain electrical activity measurements to identify changes that occur in the precuneus and its connected regions over time. Participants will also undergo comprehensive neuropsychological (memory and behavioral) testing at baseline and during follow up. Additionally, participants and their caregivers will complete brief weekly check-ins at each treatment during the study, as well as questionnaires related to the study blinding at multiple timepoints.