Restricted accessReview articleFirst published online 2025-5
A systematic review and meta-analysis on the characteristics of transcranial magnetic stimulation treatment protocols for patients with Alzheimer's disease
Alzheimer's disease (AD) is the most common neurodegenerative condition causing dementia. Currently, there has been no established non-pharmacological treatment for cognitive decline in patients with AD. Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be effective as a non-invasive treatment for improving cognitive function in AD.
Objective
This study aimed to examine the characteristics of rTMS treatment protocols for patients with AD
Methods
We conducted a systematic literature search on clinical trials on rTMS for improving cognitive decline in patients with AD, using the PubMed, PsycINFO, and Scopus databases and performed a meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. To clarify which cognitive domains in AD are improved by rTMS, meta-analyses were conducted on both global cognitive function and on each cognitive domain including verbal memory, processing speed, and executive function. In addition, sub-analyses of the treatment details of rTMS parameters including stimulation sites, stimulation frequency, stimulation intensity, and with/without the neuro-navigation technique and meta-regression analyses adjusting for gender, education, and the number of rTMS pulses were performed.
Results
The results showed significant improvements in global cognitive function, while no significant findings in verbal memory, processing speed and executive function. No significant results were found in subgroup analysis or meta-regression.
Conclusions
To enrich the evidence for cognitive enhancement in AD with rTMS, the randomized controlled trials using a unified rTMS protocol with a larger sample size are warranted.
TeselinkJBawaKKKooGK, et al.Efficacy of non-invasive brain stimulation on global cognition and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review. Ageing Res Rev2021; 72: 101499.
2.
MimuraYNishidaHNakajimaS, et al.Neurophysiological biomarkers using transcranial magnetic stimulation in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. Neurosci Biobehav Rev2021; 121: 47–59.
3.
LiXQiGYuC, et al.Cortical plasticity is correlated with cognitive improvement in Alzheimer’s disease patients after rTMS treatment. Brain Stimul2021; 14: 503–510.
4.
BremA-KDi IorioRFriedPJ, et al.Corticomotor plasticity predicts clinical efficacy of combined neuromodulation and cognitive training in Alzheimer’s disease. Front Aging Neurosci2020; 12: 200.
5.
BagattiniCZanniMBaroccoF, et al.Enhancing cognitive training effects in Alzheimer’s disease: rTMS as an add-on treatment. Brain Stimul2020; 13: 1655–1664.
6.
KochGBonnìSPellicciariMC, et al.Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer’s disease. Neuroimage2018; 169: 302–311.
7.
LiuCHanTXuZ, et al.Modulating gamma oscillations promotes brain connectivity to improve cognitive impairment. Cereb Cortex2022; 32: 2644–2656.
8.
SpeerAMKimbrellTAWassermannEM, et al.Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry2000; 48: 1133–1141.
9.
CaoTTThomsonRHBaileyNW, et al.A near infra-red study of blood oxygenation changes resulting from high and low frequency repetitive transcranial magnetic stimulation. Brain Stimul2013; 6: 922–924.
10.
SpeerAMBensonBEKimbrellTK, et al.Opposite effects of high and low frequency rTMS on mood in depressed patients: relationship to baseline cerebral activity on PET. J Affect Disord2009; 115: 386–394.
11.
HuangY-ZEdwardsMJRounisE, et al.Theta burst stimulation of the human motor cortex. Neuron2005; 45: 201–206.
12.
KishiTSakumaKMatsudaY, et al.Intermittent theta burst stimulation vs. high-frequency repetitive transcranial magnetic stimulation for major depressive disorder: a systematic review and meta-analysis. Psychiatry Res2023; 328: 115452.
13.
MenardiADottiLAmbrosiniE, et al.Transcranial magnetic stimulation treatment in Alzheimer’s disease: a meta-analysis of its efficacy as a function of protocol characteristics and degree of personalization. J Neurol2022; 269: 5283–5301.
14.
LiSLanXLiuY, et al.Unlocking the potential of repetitive transcranial magnetic stimulation in Alzheimer’s disease: a meta-analysis of randomized clinical trials to optimize intervention strategies. J Alzheimers Dis2024; 98: 481–503.
15.
ManesFJorgeRMorcuendeM, et al.A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly. Int Psychogeriatr2001; 13: 225–231.
16.
TrevizolAPGoldbergerKWMulsantBH, et al.Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Geriatr Psychiatry2019; 34: 822–827.
17.
HerbsmanTAveryDRamseyD, et al.More lateral and anterior prefrontal coil location is associated with better repetitive transcranial magnetic stimulation antidepressant response. Biol Psychiatry2009; 66: 509–515.
18.
JulkunenPSäisänenLDannerN, et al.Comparison of navigated and non-navigated transcranial magnetic stimulation for motor cortex mapping, motor threshold and motor evoked potentials. Neuroimage2009; 44: 790–795.
19.
GuoJWangZLiuR, et al.Memantine, donepezil, or combination therapy-what is the best therapy for Alzheimer’s disease? A network meta-analysis. Brain Behav2020; 10: e01831.
20.
BreijyehZKaramanR. Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules2020; 25: 5789.
21.
WithingtonCGTurnerRS. Amyloid-related imaging abnormalities with anti-amyloid antibodies for the treatment of dementia due to Alzheimer’s disease. Front Neurol2022; 13: 862369.
22.
ChouY-HTon ThatVSundmanM. A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging2020; 86: 1–10.
23.
DuboisBFeldmanHHJacovaC, et al.Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol2010; 9: 1118–1127.
24.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 270–279.
25.
KochGCasulaEPBonnìS, et al.Precuneus magnetic stimulation for Alzheimer’s disease: a randomized, sham-controlled trial. Brain2022; 145: 3776–3786.
26.
WuXJiG-JGengZ, et al.Accelerated intermittent theta-burst stimulation broadly ameliorates symptoms and cognition in Alzheimer’s disease: a randomized controlled trial. Brain Stimul2022; 15: 35–45.
27.
ZhaoJLiZCongY, et al.Repetitive transcranial magnetic stimulation improves cognitive function of Alzheimer’s disease patients. Oncotarget2017; 8: 33864–33871.
28.
VecchioFQuarantaDMiragliaF, et al.Neuronavigated magnetic stimulation combined with cognitive training for Alzheimer’s patients: an EEG graph study. Geroscience2022; 44: 159–172.
29.
RabeyJMDobronevskyEAichenbaumS, et al.Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: a randomized, double-blind study. J Neural Transm2013; 120: 813–819.
30.
ZhangFQinYXieL, et al.High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer’s disease. J Neural Transm2019; 126: 1081–1094.
31.
WeiLZhangYWangJ, et al.Parietal-hippocampal rTMS improves cognitive function in Alzheimer’s disease and increases dynamic functional connectivity of default mode network. Psychiatry Res2022; 315: 114721.
32.
YaoQTangFWangY, et al.Effect of cerebellum stimulation on cognitive recovery in patients with Alzheimer disease: a randomized clinical trial. Brain Stimul2022; 15: 910–920.
33.
HuYJiaYSunY, et al.Efficacy and safety of simultaneous rTMS-tDCS over bilateral angular gyrus on neuropsychiatric symptoms in patients with moderate Alzheimer’s disease: a prospective, randomized, sham-controlled pilot study. Brain Stimul2022; 15: 1530–1537.
34.
PadalaPRBoozerEMLensingSY, et al.Neuromodulation for apathy in Alzheimer’s disease: a double-blind, randomized, sham-controlled pilot study. J Alzheimers Dis2020; 77: 1483–1493.
35.
CotelliMCalabriaMManentiR, et al.Improved language performance in Alzheimer disease following brain stimulation. J Neurol Neurosurg Psychiatry2011; 82: 794–797.
36.
AhmedMADarwishESKhedrEM, et al.Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer’s dementia. J Neurol2012; 259: 83–92.
37.
QinYBaLZhangF, et al.Multisite rTMS combined with cognitive training modulates effective connectivity in patients with Alzheimer’s disease. Front Neural Circuits2023; 17: 1202671.
38.
SaitohYHosomiKManoT, et al.Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer’s dementia in Japan. Front Aging Neurosci2022; 14: 993306.
39.
WuYXuWLiuX, et al.Adjunctive treatment with high frequency repetitive transcranial magnetic stimulation for the behavioral and psychological symptoms of patients with Alzheimer’s disease: a randomized, double-blind, sham-controlled study. Shanghai Arch Psychiatry2015; 27: 280–288.
40.
RutherfordGLithgowBMoussaviZ. Short and long-term effects of rTMS treatment on Alzheimer’s disease at different stages: a pilot study. J Exp Neurosci2015; 9: 43–51.
41.
LeocaniLDalla CostaGCoppiE, et al.Repetitive transcranial magnetic stimulation with H-coil in Alzheimer’s disease: a double-blind, placebo-controlled pilot study. Front Neurol2020; 11: 614351.
42.
LeeJChoiBHOhE, et al.Treatment of Alzheimer’s disease with repetitive transcranial magnetic stimulation combined with cognitive training: a prospective, randomized, double-blind, placebo-controlled study. J Clin Neurol2016; 12: 57–64.
43.
JiaYXuLYangK, et al.Precision repetitive transcranial magnetic stimulation over the left parietal cortex improves memory in Alzheimer’s disease: a randomized, double-blind, sham-controlled study. Front Aging Neurosci2021; 13: 693611.
44.
MoussaviZUeharaMRutherfordG, et al.Repetitive transcranial magnetic stimulation as a treatment for Alzheimer’s disease: a randomized placebo-controlled double-blind clinical trial. Neurotherapeutics2024; 21: e00331.
45.
MartinDMMcclintockSMForsterJ, et al. Does therapeutic repetitive transcranial magnetic stimulation cause cognitive enhancing effects in patients with neuropsychiatric conditions? A systematic review and meta-analysis of randomised controlled trials. Neuropsychol Rev2016; 26: 295–309.
46.
BalsisSBengeJFLoweDA, et al.How do scores on the ADAS-Cog, MMSE, and CDR-SOB correspond?Clin Neuropsychol2015; 29: 1002–1009.
47.
FerrettiMTIulitaMFCavedoE, et al.Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol2018; 14: 457–469.
48.
ToroCAZhangLCaoJ, et al.Sex differences in Alzheimer’s disease: understanding the molecular impact. Brain Res2019; 1719: 194–207.
49.
SharpESGatzM. Relationship between education and dementia: an updated systematic review. Alzheimer Dis Assoc Disord2011; 25: 289–304.
50.
HigginsJPTAltmanDGGøtzschePC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ2011; 343: d5928.
51.
PiniLPizziniFBBoscolo-GalazzoI, et al.Brain network modulation in Alzheimer’s and frontotemporal dementia with transcranial electrical stimulation. Neurobiol Aging2022; 111: 24–34.
52.
DennisELThompsonPM. Functional brain connectivity using fMRI in aging and Alzheimer’s disease. Neuropsychol Rev2014; 24: 49–62.
53.
XieYLiYNieL, et al.Cognitive enhancement of repetitive transcranial magnetic stimulation in patients with mild cognitive impairment and early Alzheimer’s disease: a systematic review and meta-analysis. Front Cell Dev Biol2021; 9: 734046.
54.
FernandesSMMendesAJRodriguesPFS, et al.Efficacy and safety of repetitive transcranial magnetic stimulation and transcranial direct current stimulation in memory deficits in patients with Alzheimer’s disease: meta-analysis and systematic review. Int J Clin Health Psychol2024; 24: 100452.
55.
KochGSpampinatoD. Alzheimer disease and neuroplasticity. Handb Clin Neurol2022; 184: 473–479.
56.
ZhouJSeeleyWW. Network dysfunction in Alzheimer’s disease and frontotemporal dementia: implications for psychiatry. Biol Psychiatry2014; 75: 565–573.
57.
SomanSMRaghavanSRajeshPG, et al.Does resting state functional connectivity differ between mild cognitive impairment and early Alzheimer’s dementia?J Neurol Sci2020; 418: 117093.
58.
CheyuoCGermannJYamamotoK, et al.Connectomic neuromodulation for Alzheimer’s disease: a systematic review and meta-analysis of invasive and non-invasive techniques. Transl Psychiatry2022; 12: 490.
59.
LiaoL-YZhangY-QLauBW-M, et al.A pilot study on the repetitive transcranial magnetic stimulation of Aβ and tau levels in rhesus monkey cerebrospinal fluid. J Vis Exp2021; (175). doi: 10.3791/63005.
60.
BokJHaJAhnBJ, et al.Disease-modifying effects of non-invasive electroceuticals on β-amyloid plaques and tau tangles for Alzheimer’s disease. Int J Mol Sci2022; 24: 679.
61.
RicciMRuggeriMGnisciC, et al.Improving amnesia diagnostic accuracy with RAVLT single scores and composite indices: Italian Normative Data. Arch Clin Neuropsychol2022; 37: 1749–1764.
62.
GiffordKALiuDNealJE, et al.The 12-Word Philadelphia Verbal Learning Test performances in older adults: Brain MRI and cerebrospinal fluid correlates and regression-based normative data. Dement Geriatr Cogn Dis Extra2018; 8: 476–491.
63.
ScovilleWBMilnerB. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry1957; 20: 11–21.
64.
MaeshimaSOsawaA. Memory impairment due to stroke. In: DehkharghaniS (ed.) Stroke. Brisbane (AU): Exon Publications, 2021 Jun 18. Chapter 6.
65.
PutchaDBrickhouseMWolkDA, et al.Fractionating the Rey Auditory Verbal Learning Test: distinct roles of large-scale cortical networks in prodromal Alzheimer’s disease. Neuropsychologia2019; 129: 83–92.
66.
Rashidi-RanjbarNRajjiTKHawcoC, et al.Association of functional connectivity of the executive control network or default mode network with cognitive impairment in older adults with remitted major depressive disorder or mild cognitive impairment. Neuropsychopharmacology2023; 48: 468–477.
67.
NorthoffGSibilleE. Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings. Mol Psychiatry2014; 19: 966–977.
68.
JackCRJrAndrewsJSBeachTG, et al.Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s association workgroup. Alzheimers Dement2024; 20: 5143–5169.
