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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
40
This is an early phase study investigating the effects of rTMS on individuals with early AD.
sham rTMS
Baylor College of Medicine
Houston, Texas, United States
RECRUITINGMMSE
The Mini-Mental State Examination (MMSE) is a widely used 30-point cognitive assessment tool that helps assess domains such as orientation, memory, attention, language and visuospatial skills. It is often used in neurology, geriatrics and clinical research to screen for cognitive impairment and to monitor changes over time. The maximum score is 30 points. The minimum score is 0. A 27-30 score is considered normal range, though subtle cognitive issues may still exist. A 24-26 score may indicate mild cognitive concerns A 20-23 score may be suggestive of mild cognitive impairment or mild dementia A 10-19 score may be suggestive of moderate cognitive impairment A score of less than 10 may be suggestive of severe cognitive impairment
Time frame: immediate, 3-months post rTMS, 6-months post rTMS
Clinical Dementia Rating scale (CDR)
The Clinical Dementia Rating (CDR) Scale is a clinician-rated staging instrument that assesses the severity of cognitive impairment based on both patient performance and information from an informant (e.g., caregiver or family member). The maximum score is 18. The minimum score is 0. A score of 16-18 indicates severe dementia A score of 9.5-15.5 indicates moderate dementia A score of 4.5-9.0 indicates mild dementia A score of 0.5-4.0 indicates very mild impairment A score of 0 indicates no impairment
Time frame: immediate, 3-months post rTMS, 6-months post rTMS
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)
The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a measure of cognitive impairment. The maximum score if 70. The minimum score is 0. 0-10 Little or no detectable cognitive impairment 10-20 Mild cognitive impairment or very mild dementia 20-35 Mild to moderate Alzheimer's disease 35-50 Moderate to severe cognitive impairment \>50 Severe cognitive impairment
Time frame: immediate, 3-months post rTMS, 6-months post rTMS
Verbal learning test
The Verbal Learning Test measure episodic verbal memory-the ability to learn, retain, and retrieve spoken information. The maximum score is 75. The minimum score is 0. Higher scores indicate better memory retention. 60-75 Excellent learning 45-59 Average to mildly reduced 30-44 Mild to moderate impairment 15-29 Moderate impairment 0-14 Severe impairment
Time frame: immediate, 3-months post rTMS, 6-months post rTMS
Boston Naming Test
The Boston Naming Test (BNT) is a widely used neuropsychological assessment that measures confrontation naming-the ability to retrieve and produce the correct name for a visually presented object. The maximum sore is 60. The minimum score if 0. 55-60 Excellent naming ability 50-54 Average to mildly reduced 40-49 Mild naming impairment 30-39 Moderate naming impairment \<30 Significant naming impairment
Time frame: immediate, 3-months post rTMS, 6-months post rTMS
Trail making test
The Trail Making Test (TMT) is a widely used neuropsychological test that measures processing speed, visual attention, sequencing, mental flexibility, and executive function. The score is the time it takes to complete the task. Lower times are better, while longer times indicate greater impairment. The minimum score is less than 30 seconds. The maximum score is greater than 300 seconds. \<30 seconds Excellent 30-45 seconds Average 46-78 seconds Mild slowing 79-120 seconds Moderate impairment \>120 seconds Significant impairment
Time frame: immediate, 3-months post rTMS, 6-months post rTMS
Digital Span
The Digit Span test is a brief neuropsychological assessment that measures attention, concentration, immediate memory, and working memory. The maximum score if 9. The minimum score is 0. 7-9 digits Excellent attention 6 digits Average 5 digits Low average 4 digits Mild impairment ≤3 digits Significant impairment
Time frame: immediate, 3-months post rTMS, 6-months post rTMS
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