Alzheimer’s disease and the therapeutic potential of theta burst stimulation: A systematic review of preclinical and clinical studies

Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral impairment. Despite growing research efforts, effective disease-modifying interventions remain elusive. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), has shown promise in modulating cortical excitability, synaptic plasticity, and neuroprotective mechanisms. This systematic review aimed to evaluate the efficacy and safety of TBS in AD by synthesizing findings from preclinical and clinical studies.

A systematic search of PubMed, Scopus, Embase, Web of Science, and the Cochrane Library was conducted up to January 2025. Studies investigating TBS, including intermittent TBS [iTBS] and continuous TBS [cTBS], in human patients with AD or in animal models of AD were included. Primary outcomes included cognitive function and neuropsychiatric symptoms. Secondary outcomes included biomarkers of neuroplasticity and neurodegeneration. The risk of bias was assessed using the Joanna Briggs Institute (JBI) and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tools.

Twenty studies met the inclusion criteria, comprising six preclinical and 14 clinical studies. Preclinical evidence suggests that TBS reduces amyloid-beta deposition, enhances synaptic plasticity, mitigates neuroinflammation and oxidative stress, and improves cognitive performance in animal models of AD. iTBS targeting the dorsolateral prefrontal cortex (DLPFC) improved cognitive function, depression, anxiety, and activities of daily living, with some studies reporting non-significant findings in specific neuropsychological assessments. Neuroplasticity changes were observed in motor-evoked potentials and resting motor thresholds, with lower responses in patients with AD and variable reproducibility over time. Additionally, structural and functional brain changes, including preserved hippocampal volume and enhanced frontal beta activity, were associated with cognitive improvements. Adverse events were mild and well-tolerated.

Preclinical studies robustly support the neuroprotective and neuropsychiatric effects of TBS in AD models. Clinical findings suggest possible benefits of TBS, particularly iTBS over the DLPFC; however, clinical results are inconsistent and limited by small sample sizes and protocol variability. These findings highlight the challenges of translating animal data to humans and underscore the need for larger, controlled randomized clinical trials to confirm safety and efficacy and optimize treatment parameters. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted as a systematic review. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study, which was conducted as a systematic review. List of abbreviation - Aβ - Amyloid-beta - AD - Alzheimer’s disease - ADAS-Cog - Alzheimer’s Disease Assessment Scale-Cognitive Subscale - ADL - Activities of Daily Living - Akt - Protein kinase B - AMPA - α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid - APP - Amyloid precursor protein - AVLT - Auditory Verbal Learning Test - BACE1 - β-Site amyloid precursor protein cleaving enzyme 1 - BDNF - Brain-derived neurotrophic factor - BNT - Boston Naming Test - CD68 - Cluster of differentiation 68 - CDR - Clinical Dementia Rating - CDT - Clock-Drawing Test - cTBS - Continuous theta burst stimulation - DLPFC - Dorsolateral prefrontal cortex - DST - Digit Span Test - ERK1/2 - Extracellular signal-regulated kinases 1 and 2 - GFAP - Glial fibrillary acidic protein - GMV - Gray matter volume - GSH - Glutathione - HAMA - Hamilton Anxiety Scale - HAMD/HDRS - Hamilton Depression Rating Scale - Iba1 - Ionized calcium-binding adapter molecule 1 - ICF - Intracortical facilitation - IDE - Insulin-degrading enzyme - IFN-γ - Interferon-gamma - IL-1β - Interleukin-1 beta - IL-6 - Interleukin-6 - iTBS - Intermittent theta burst stimulation - JBI - Joanna Briggs Institute - M1 - Primary motor cortex - MDA - Malondialdehyde - MEP - Motor evoked potential - MnSOD - Manganese superoxide dismutase - MMSE - Mini-Mental State Examination - MoCA - Montreal Cognitive Assessment - mTOR - Mammalian target of rapamycin - NeuN - Neuronal nuclei - NMDA - N-methyl-D-aspartate - NPI - Neuropsychiatric Inventory - NO2− - Nitrite - PI3K - Phosphoinositide 3-kinase - PROSPERO - International Prospective Register of Systematic Reviews - PRISMA - Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PSD95 - Postsynaptic density protein 95 - QoL-AD - Quality of Life in Alzheimer’s Disease - RBANS - Repeatable Battery for the Assessment of Neuropsychological Status - rMT - Resting motor threshold - rTMS - Repetitive transcranial magnetic stimulation - SCWT - Stroop Color-Word Test - SICI - Short-interval intracortical inhibition - SLAI - Short-latency afferent inhibition - SNAP25 - Synaptosomal-associated protein 25 - SYRCLE - Systematic Review Centre for Laboratory Animal Experimentation - SYN1 - Synapsin-1 - TBS - Theta burst stimulation - TMT - Trail Making Test - TNF-α - Tumor necrosis factor-alpha - tSOD - Total superoxide dismutase - VAMP1 - Vesicle-associated membrane protein 1 - VFT - Verbal Fluency Test.