The goal of this clinical trial is to learn if repetitive transcranial magnetic stimulation (rTMS), a non-invasive form of brain stimulation, can improve short-term memory in people with early Alzheimer's disease (AD). The study will also evaluate the safety of this approach.

The main questions it aims to answer are:

• Does rTMS applied to the cerebellum improve short-term memory in people with early AD?
• How does this stimulation affect brain activity and connectivity measured by MRI?

Researchers will compare active rTMS to sham rTMS (a look-alike procedure that does not deliver brain stimulation) to see if rTMS works to improve memory.

Participants will:

• Complete a screening visit with medical and memory assessments
• Be randomly assigned to receive either active rTMS or sham rTMS (neither participants nor researchers will know the assignment during treatment)
• Receive 20 rTMS sessions over 4 weeks (about 20 to 30 minutes per session)
• Undergo two MRI scans, one before and one after treatment
• Complete memory and thinking tests and questionnaires at baseline, immediately after treatment, and at 3- and 6-month follow-up visits

Participation in the study will last about 6 months.

The rTMS is generally well tolerated. The most common side effects include mild headache and scalp discomfort during treatment, which are usually short-lasting. MRI is non-invasive and safe for most people. Study procedures will be reviewed to ensure participant safety.

Participants may or may not benefit directly from this study. People who receive active rTMS may experience improvement in memory. This research may help improve understanding of memory function in AD and support development of new treatments.

Background and Rationale

• AD is a progressive neurodegenerative disorder characterized by cognitive decline, including impairments in memory. Emerging evidence suggests that the cerebellum, which is relatively spared in early AD pathology, may contribute to memory processes through its functional connectivity with cortical regions such as the posterior cingulate cortex. This raises the possibility that modulation of cerebellar activity may influence memory performance in individuals with AD.
• rTMS is a non-invasive neuromodulation technique that uses magnetic pulses to alter cortical excitability and network activity. rTMS is approved for the treatment of major depressive disorder and has been investigated in other neurological conditions. Its safety profile is well established, with commonly reported side effects including mild headache, scalp discomfort, and transient sensory effects.
• This study evaluates whether cerebellar-targeted rTMS can improve short-term memory and modulate brain activity in individuals with early AD.

Study Objectives

• The primary objective of this study is to determine whether rTMS applied to the cerebellum improves short-term memory in individuals with early AD.
• Secondary objectives include: i) evaluating changes in brain activity and functional connectivity using functional magnetic resonance imaging (fMRI), and ii) Assessing the safety and tolerability of cerebellar rTMS in this population

Study Design: this is a randomized, double-blind, sham-controlled clinical trial. Approximately 40 participants with early AD will be enrolled. Participants will be randomized in a 1:1 ratio to receive either active rTMS or sham stimulation. Both participants and study personnel involved in outcome assessment will be blinded to treatment assignment. The total duration of participation is approximately 6 months.

Study Procedures

• Screening and Baseline Assessments: At the screening visit, eligibility will be confirmed through review of medical history, current medications, and inclusion/exclusion criteria. Baseline assessments will include:
• Functional magnetic resonance imaging (fMRI)
• Cognitive and memory assessments, including standardized measures of global cognition, memory, executive function, attention, and processing speed Self-report questionnaires assessing behavioral and cognitive function Intervention Phase (rTMS Treatment)
• Cerebellar rTMS: Participants will undergo 20 rTMS sessions administered over 4 weeks (5 sessions per week). Each session will last approximately 20-30 minutes. rTMS will be applied to the cerebellum using a non-invasive magnetic stimulation device. Participants will be randomized to receive either i) Active rTMS targeting the cerebellum, or ii) Sham rTMS designed to mimic the procedure without delivering active stimulation. An fMRI scan will be conducted at the start of the intervention phase and again after completion of the 20 treatment sessions.
• Post-Treatment and Follow-Up Assessments: at the conclusion of the 20 rTMS sessions, participants will undergo repeat fMRI imaging, repeat cognitive and memory assessments.
• The above follow-up visits will occur at 3 months and 6 months post-intervention. These visits will include repeated cognitive and behavioral assessments to evaluate the durability of treatment effects.

Outcome Measures will include changes in cognitive performance (with an emphasis on memory function) and changes in brain activity and connectivity as measured by fMRI.

Safety Monitoring

• rTMS is generally well tolerated. The most commonly reported side effects include mild headache, scalp discomfort, and transient sensory effects such as facial muscle twitching or auditory discomfort. MRI procedures are non-invasive and considered safe for eligible participants.
• Participant eligibility will be carefully assessed to minimize risk, and safety will be monitored throughout the study.

Inclusion Criteria:

Participants must meet all of the following inclusion criteria to be eligible for enrollment:

• A clinical diagnosis of early AD, defined as either mild cognitive impairment (MCI) due to AD or mild dementia due to AD;
• Evidence of cognitive impairment, characterized by a MMSE score between 20 and 28 and/or a CDR-Sum of Boxes score between 0.5 and 8, consistent with the contemporary definitions used in early AD in clinical trials; and
• Biomarker confirmation of AD pathology, demonstrated by a positive plasma phosphorylated tau-217 (p-tau217) result according to the 2024 National Institute on Aging-Alzheimer's Association (NIA-AA) diagnostic guidelines.

Exclusion Criteria:

• Exclusion criteria include evidence of other neurological, psychiatric, or systemic conditions that could cause cognitive and functional impairments (e.g., substantial concomitant cerebrovascular disease, alcoholism, certain medications that could have a substantial effect on cognition, untreated major depressive disorder, and heart, renal or hepatic failure).
• Individuals who have contraindications to receiving rTMS, including a history of seizures or any non-removable metal in their heads or within 12 inches of the TMS coil will be excluded.

At this time, this is a pilot investigator initiated study with no intentions of sharing individual participant data with any other researchers.

Research coordinators will also be masked.