NON-INVASIVE BRAIN STIMULATION FOR MEMORY LOSS IN EARLY ALZHEIMER'S DISEASE

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.