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

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.

Inclusion criteria

• Agreement to participate in study and able to complete informed consent process
• Have a caregiver or study partner who can accompany them to all study visits
• Have a known alternate surrogate decision-maker (in case needed) who can be present for informed consent
• Established diagnosis of biomarker-positive (amyloid-PET, plasma or CSF amyloid ratio or phosphorylated tau) mild-moderate (clinical stages 3, 4, and 5) Alzheimer's Disease based on the 2024 Alzheimer's Association Framework
• Age 55-100 at the start of the study.
• Screening MOCA 12-25 (< 26, > 11)
• Screening GDS score <6
• Either 1) treated with memory-enhancing medication (cholinesterase inhibitor or other medications or treatments) for at least 2 months, 2) failed trial with no plan to re-trial, or 3) no trial planned during the course of the study for other reasons
• No change in use of psychotropic medication (or other treatments) for the treatment of depression, anxiety, ADHD, or psychosis for 2 weeks prior to the study

Exclusion criteria

• Unwilling or unable to provide informed consent as outlined below
• Currently pregnant or potentially pregnant
• Diagnosis of a dementia or cognitive disorder primarily or exclusively due to a cause other than Alzheimer's Disease
• Diagnosis of severe Dementia (CDR > 2.0/ AA clinical stage 6) at the start of the study
• History of substance use disorder currently not in sustained remission
• Substance misuse within the past 6 months (excluding nicotine or caffeine)
• History of stroke, traumatic brain injury with loss of consciousness, or other major neurologic disorder (e.g., epilepsy, Huntington's disease, Parkinson's disease)
• History of seizure disorder or family history of seizure disorder in a first-degree relative
• Poorly-controlled hypertension, cardiovascular disease, or cerebrovascular disease
• History of any other major active medical, neurologic, or psychiatric illness affecting cognition (associated with cognitive impairment) or a participant's ability to safely and meaningfully participate in the study
• Non-fluent in English (not native or functionally-native, specified here for cognitive testing purposes)
• Contraindication to TMS or MRI including claustrophobia, MRI-incompatible or unknown metal in body (including facial tattoos with uknown or metallic inks), surgery within 60 days, certain implants (excluding dental fillings), or previous abnormal MRI results unrelated to a potential participant's dementia.
• For the randomized stage only-has a history of prior TMS treatment (not TMS naïve)
• Currently enrolled in an interventional memory-enhancement study
• Alteration in cognitive-enhancement medication (or other treatment) dose within the past 2 months or active plans for dose alteration during the course of the study (previously unplanned changes that occur during the study will be examined on a case-by-case basis)
• Has started treatment with lecanemab, donanemab, or any other monoclonal antibody for Alzheimer's Disease within the past 6 months OR has a history of treatment complicated by amyloid-related imaging abnormalities (ARIA)
• Currently or within the past 2 weeks taking any of the following classes of medication:

• Anticholinergic (e.g., tolterodine, benztropine)
• Sedating antihistamines (e.g., diphenhydramine)
• any drug that has significant anticholinergic or antihistaminic side effects (e.g., tricyclic antidepressant medications, mirtazapine).
• Benzodiazepines. While not a strict rule out, this will be decided on a case-by-case basis
• Opioid. While not a strict rule out, this will be decided on a case-by-case basis
• Antiepileptic agents. While not a strict rule out, this will be decided on a case-by-case basis
• Antipsychotic agents. While not a strict rule out, this will be decided on a case-by-case basis