The goal of this clinical trial is to learn if using deep repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus is feasible, tolerable, and potentially efficacious for memory in Probable Alzheimer's Dementia. 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-to-moderate probable Alzheimer's Dementia.

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 4 once weekly maintenance sessions
• 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-phase 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 phase will be a handful of subjects (5-10) receiving active treatment only to refine the protocol. After refinement, the second phase will consist of a randomized, double-blind, sham controlled clinical trial with post-blinding crossover 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.

Participants will undergo 16 total rTMS brain stimulation sessions (each session being about 20 minutes) over the course of 5 weeks. The initial induction 3-day intensive course in which rTMS (or sham) will be applied four times daily with 1-hour breaks between treatments will be followed by a 4-week maintenance course in which stimulation will be applied once weekly.

Participants will undergo a range of assessments including brain imaging and oxygenation, genotyping, eye reactivity to light testing, 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.

Inclusion Criteria:

• Age 60-100 at the start of the study
• Established diagnosis of Alzheimer's Clinical Syndrome (which is also met through a diagnosis of Alzheimer's Dementia)
• Agreement to participate in study and able to complete informed consent process
• Have a caregiver/study partner who can accompany them to all study visits
• Have a known alternate surrogate decision-maker (in case needed) who can accompany them to the informed consent visit (this person may be the study partner mentioned above)
• Screening MMSE score of 18-26
• Screening GDS score <6
• Either 1) treated with memory-enhancing medication (cholinesterase inhibitor) 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 for the treatment of depression, anxiety, ADHD, or psychosis for 2 weeks prior to the study

Exclusion Criteria:

• Participant and/or their surrogate are unwilling or unable to provide informed consent

• Currently pregnant or potentially pregnant

• Diagnosis of a dementia or cognitive disorder due to a cause other than Alzheimer's Disease

• Diagnosis of severe Dementia (CDR > 2.0) 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)

• 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.

• Has previous history of TMS treatment in the past (not TMS naïve)

• Currently enrolled in a memory-enhancement study

• Alteration in cognitive-enhancement medication 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)

• History of treatment with lecanemab, aducanumab, donanemab, or other monoclonal antibody treatment for Alzheimer's Disease (due to lack of knowledge surrounding the impacts of these treatments)

• 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
  • 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

Demographics, neuropsychological outcomes, pupillary reactivity, 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.

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

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.