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

September 1, 2026 updated by: Michael K Leuchter, University of California, Los Angeles

Protocol for Maintaining and Improving Mental Status in Alzheimer's Disease (PROMIS-AD): a Pilot Study of Large-Coil Parietal Repetitive Transcranial Magnetic Stimulation for Alzheimer&Amp;Amp;#39;s Disease

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

54

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • UCLA TMS Clinical and Research Service
        • Contact:
        • Contact:
        • Principal Investigator:
          • Michael Leuchter, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Open-Label Active deep rTMS (First Study Stage)

The first stage of the study will consist of protocol refinement. In this first stage of 5-10 participants, all participants will receive open-label active treatment.

Treatment will consist of 16 sessions of deep rTMS spread over 5 weeks. The induction phase of treatment will be 4 sessions per day for 3 consecutive days (with 60 minutes between sessions), followed by 1 session per week for 4 weeks.

Individual sessions will consist of 1600 pulses of 20Hz rTMS delivered in 40 pulse trains to the precuneus (using MRI structural neuronavigation) at 100% of depth-corrected motor-threshold with a 28 second intertrain interval (roughly 20 minutes per session).
Device: TMS
rTMS Stimulation Parameters Pulse count: 1600 pulses Frequency: 20Hz Pules per train: 40 pulses Inter-train interval: 20 seconds (28s originally) Intensity: 100% Motor Threshold (depth-corrected from MRI) Target: Precuneus using structural MRI navigation with MNI coordinates
Other Names:
  • precuneus deep repetitive transcranial magnetic stimulation
Experimental: Randomized Active deep precuneus rTMS
The second stage of the study will consist of both active and sham treatment groups. Treatment will consist of 28 sessions of deep rTMS spread over 9 weeks. The induction phase of treatment will be 4 sessions per day for 3 consecutive days (with 30-60 minutes between sessions), followed by 1 visit per week (with two sessions per visit separated by 30-60 minutes) for 8 weeks. Individual sessions will consist of 1600 pulses of 20Hz rTMS delivered in 40 pulse trains to the precuneus (using MRI structural neuronavigation) at 100% of depth-corrected motor-threshold with a 20 second intertrain interval (roughly 15-20 minutes per session). The active group will receive this protocol using an active treatment coil delivering real rTMS.
Device: TMS
rTMS Stimulation Parameters Pulse count: 1600 pulses Frequency: 20Hz Pules per train: 40 pulses Inter-train interval: 20 seconds (28s originally) Intensity: 100% Motor Threshold (depth-corrected from MRI) Target: Precuneus using structural MRI navigation with MNI coordinates
Other Names:
  • precuneus deep repetitive transcranial magnetic stimulation
Sham Comparator: Randomized Sham deep precuneus rTMS

The second stage of the study will consist of both active and sham treatment groups. Treatment will consist of 28 sessions of deep rTMS spread over 9 weeks. The induction phase of treatment will be 4 sessions per day for 3 consecutive days (with 30-60 minutes between sessions), followed by 1 visit per week (with two sessions per visit separated by 30-60 minutes) for 8 weeks. Individual sessions will consist of 1600 pulses of 20Hz rTMS delivered in 40 pulse trains to the precuneus (using MRI structural neuronavigation) at 100% of depth-corrected motor-threshold with a 20 second intertrain interval (roughly 15-20 minutes per session). The placebo group will receive this protocol using a sham TMS coil delivering inactive rTMS.

Participants in the sham/placebo group will be offered a full open-label extension treatment course of active rTMS on completion of the randomized phase.
Device: Transcranial Magnetic Stimulation Sham
Sham coil placed in same location and set with same parameters as active treatment coil. However, this device will not output active treatment and scalp electrodes will mimic the sensation of rTMS for the participant.
Device: TMS
rTMS Stimulation Parameters Pulse count: 1600 pulses Frequency: 20Hz Pules per train: 40 pulses Inter-train interval: 20 seconds (28s originally) Intensity: 100% Motor Threshold (depth-corrected from MRI) Target: Precuneus using structural MRI navigation with MNI coordinates
Other Names:
  • precuneus deep repetitive transcranial magnetic stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Completion Rate
Time Frame: From enrollment to the end of treatment after 9 weeks
The percentage/fraction of participants who complete the full course of study treatment
From enrollment to the end of treatment after 9 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse Events
Time Frame: From enrollment until the end of treatment at 9 weeks
The incidence of adverse events/side effects during the course of study treatment. Known common side effects of rTMS for other indications include discomfort/pain at the site of stimulation and mild transient headaches. Known rare though serious side effects include seizure (generally 1 in 30,000)
From enrollment until the end of treatment at 9 weeks
Gray Matter Volume
Time Frame: From pre-treatment baseline structural MRI to post-treatment structural MRI after 9 weeks.
There are indications rTMS may preserve gray matter volume in neurodegenerative disease near the site of stimulation and connected areas. Volume of the precuneus, stimulated areas, and connected areas will be studied before and after treatment.
From pre-treatment baseline structural MRI to post-treatment structural MRI after 9 weeks.
White Matter Volume
Time Frame: From pre-treatment baseline structural MRI to post-treatment structural MRI after 9 weeks.
There are indications rTMS may preserve white matter volume in neurodegenerative disease near the site of stimulation and connected areas. Volume of the precuneus, stimulated areas, and connected areas will be studied before and after treatment.
From pre-treatment baseline structural MRI to post-treatment structural MRI after 9 weeks.
EEG
Time Frame: From pre-treatment EEG to post-treatment EEG after 9 weeks
Beta and Gamma Oscillatory power, as well as Beta/Theta periodic power ratios will be examined.
From pre-treatment EEG to post-treatment EEG after 9 weeks
NIH Cognitive Toolbox
Time Frame: Enrollment to end of 9 weeks of treatment
The NIH Cognitive Toolbox consists of a battery of tests well-validated for memory testing. Participants will undergo testing with the executive functioning tasks from this tool before and after completing treatment.
Enrollment to end of 9 weeks of treatment
resting-state functional MRI connectivity
Time Frame: from enrollment to the end of treatment at 9 weeks
Participants will undergo resting-state functional blood-oxygen-level dependent (BOLD) MRI (rs-fMRI) to examine functional connectivity between the precuneus and other areas of the brain, particularly within the default mode network
from enrollment to the end of treatment at 9 weeks
Repeatable Battery for the Assessment of Neuropsychological Status Update (RBANS Update)
Time Frame: From pre-treatment to post-induction pre-maintenance to end-of-treatment after 9 weeks.
The RBANS Update is a well-established neuropsychological test for memory. Participants will undergo testing with the RBANS before treatment, between induction and maintenance treatment, and after completing treatment. Scores range from 40 to 160, with higher scores indicating better performance and lower scores indicating worse performance.
From pre-treatment to post-induction pre-maintenance to end-of-treatment after 9 weeks.
Clinical Dementia Rating Scale (CDR)
Time Frame: From enrollment to the end of treatment at 9 weeks
CDR score and CDR-SB (sum of boxes score) are gathered from the CDR, an interview-based measure of global dementia severity. Participants and caregivers engage in interview. Global scores range from 0 to 3 with higher scores indicating greater severity of dementia. Sum of boxes scores range from 0 to 18 with higher scores indicating greater severity of dementia.
From enrollment to the end of treatment at 9 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neuropsychiatric Inventory (NPI)
Time Frame: From enrollment to the end of treatment at 9 weeks
Participants and caregivers engage in comprehensive interview to assess the presence and severity of ten behavioral and two neurovegetative symptoms common in AD. This will aid in assessment of behavioral and emotional domains
From enrollment to the end of treatment at 9 weeks
ADL/IADL
Time Frame: From enrollment to the end of treatment at 9 weeks
Participants and caregivers engage in a discussion of participant's ability to complete and/or level of assistance needed to complete everyday tasks. This will aid in assessment of everyday function and overall dependence on others.
From enrollment to the end of treatment at 9 weeks
Peripheral Tau and Amyloid levels
Time Frame: from enrollment to end of treatment at 9 weeks
Participants will undergo a blood draw for the purpose of determining peripheral Tau and Amyloid burden as a potential marker of AD pathology and allow researchers to explore potential changes with treatment.
from enrollment to end of treatment at 9 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, Los Angeles

Collaborators

National Institute on Aging (NIA)

Investigators

  • Principal Investigator: Michael Leuchter, MD, MSc, University of California, Los Angeles

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 17, 2024

Primary Completion (Estimated)

October 1, 2029

Study Completion (Estimated)

December 1, 2029

Study Registration Dates

First Submitted

September 11, 2024

First Submitted That Met QC Criteria

September 13, 2024

First Posted (Actual)

September 19, 2024

Study Record Updates

Last Update Posted (Actual)

September 4, 2026

Last Update Submitted That Met QC Criteria

September 1, 2026

Last Verified

September 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 24-000811
  • K23AG097987 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Demographics, neuropsychological outcomes, blinding validation, tau and amyloid levels, APOE status, EEG, MRI.

EEG and imaging data may not include raw EEG or imaging data, but will likely instead consist of data extracted from EEGs and MRIs.

IPD Sharing Time Frame

Beginning within 12 months of publishing results and ending no sooner than 3 years after publication of results.

IPD Sharing Access Criteria

After completion of the study, de-identified data may be made available to other institutions or secure online databases on reasonable request (such as Clinical Study Data Request, https://www.clinicalstudydatarequest.com). All other data will be handled the same way it is handled during the study.

IPD Sharing Supporting Information Type

  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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