One in three people living past 85 get Alzheimer’s Disease. There is no cure, and patients are faced with an inexorable decline that nothing can stop but death.
Transcranial Magnetic Stimulation, or TMS, is one of very few treatments that might alter this grim trajectory. Since the evidence in the scientific journals is extremely lengthy, complex and often hidden behind paywalls, I will attempt to gather, assess, and summarise it for you here, while remaining as brief and clear as possible.
The underlying science behind Alzheimer’s
The microscopic hallmarks of Alzheimer’s are degenerating neurons along with extracellular deposits of amyloid β-protein (Aβ), and intracellular clumps of tau protein that disrupt microtubule structure . Together these make the characteristic “plaques and tangles” of Alzheimer’s Disease. The greatest risk factor for Alzheimer’s is age. The strongest genetic risk is the ε4 allele of the APOE gene [11,14].
Existing medications may temporarily reduce the symptoms, but none alter the underlying progression of disease. The drugs leave existing plaques and tangles intact, and do not prevent new ones from forming. The search is underway for treatments that attack these deeper processes.
Drugs under investigation include some that act to remove the plaques, but even these may be acting at a point too late in the chain. Imagine, for example, a medication that removes the build-up of tar in a smoker’s lungs. That might reduce the chance of lung cancer, but far better would be stopping the smoke from reaching the lungs in the first place.
Alzheimer’s and the TMS
For Alzheimer’s, the ideal treatment would alter the trajectory of decline in at-risk individuals before symptoms arrive. It is during this window, which often spans decades, where TMS may have a major role.
TMS delivers waves of a high-intensity magnetic field to the cerebral cortex. Repetitive TMS (rTMS) is delivered as repeated short, high-frequency bursts in daily sessions over several weeks.
rTMS was initially approved for treatment-resistant depression after a series of trials showed solid evidence of safety and efficacy. Since then, TMS has been tried for a variety of difficult conditions – including Alzheimer’s Disease.
The first question for researchers was to select the type of TMS. Low-frequency rTMS inhibits cortical activity, whereas high-frequency (> 3Hz) increases it .
Alzheimer’s trials have mostly employed high-frequency TMS, usually at 10 or 20 Hz. TMS is delivered as an initial phase (e.g. five times per week for three weeks) and often a maintenance phase (e.g. weekly for three months).
Many studies have added cognitive exercises tailored to engage the brain regions under stimulation, hoping to enhance the effect. High-frequency repetitive TMS with cognitive exercises is abbreviated to rTMS-cog. Future research may look at the variety of other TMS variables which might have an influence, such as the shape of the coil, the distance to cortex, and the area of stimulation.
Published studies results on TMS for Alzheimer’s Disease
The following are the results of major published studies on TMS for Alzheimer’s Disease (AD), and mild cognitive impairment (MCI).
- Mild & moderate AD participants received 20 Hz TMS over the dorsolateral prefrontal cortex (DLPFC). Improved auditory comprehension and object naming was seen immediately and after 8 weeks. Other measures such as daily function and overall cognition were unchanged. (Cotelli et al., 2006, 2008)
- AD patients received either 20 Hz or sham stimulation over the precuneus. Episodic memory improved in the treatment but not sham group. (Koch et al., 2018).
- 34 MCI patients. rTMS 10 Hz vs sham. Improved cognitive scores that were sustained for at least a month. (Drumond et al., 2015)
- rTMS-cog (10Hz) over 4.5 months. Improved cognitive scores after 6 weeks and 4.5 months. (Bentwich et al., 2011)
- 20 Hz, 1Hz or sham TMS. 20 Hz improved in cognitive tests, lasting up to 3 months. No improvements in severe AD. (Ahmed et al., 2012)
- 100 controls and 8 MCI patients. Recognition memory improved after 1 Hz stimulation over the right DLPFC. (Turriziani et al., 2012)
- rTMS-cog (10Hz) over 4.5 months. Improved cognitive scores after 6 weeks and 4.5 months. (Rabey et al., 2013)
- rTMS (10 Hz) over the inferior frontal gyrus. Some cognitive tests improved but not others. (Eliasova et al., 2014)
- rTMS-cog (20Hz) for 4 weeks then 2 weeks every 3 months. Cognitive tests improved relative to expected decline. (Rutherford et al., 2015)
- rTMS-cog (10Hz) for 6 weeks. Improved cognitive scores after treatment. (Rabey and Dobronevsky, 2016)
- rTMS-cog (10Hz) for 6 weeks. Improvement in cognitive scores after treatment, but improvement also seen in the sham group. (Lee et al., 2016)
- 2 MCI, 1 mild, and 4 moderate-to-severe. rTMS-cog (10Hz) over 4.5 months. Improved cognitive, motor and apathy / independence scores that returned to baseline 6 months after treatment. (Nguyen et al., 2017)
- 30 mild to moderate patients. 20 Hz rTMS vs sham over 6 weeks. Cognitive, memory and language improved more than sham group. (Zhao et al., 2017)
Discussing the evidence
The overall pattern of these studies is that TMS, especially with the addition of cognitive exercises, has a clear positive effect, and this can maintained for at least several months by booster sessions. The benefit is most apparent for patients with mild impairment.
One potential confounding factor is the impact of TMS on underlying depression. Here two points are crucial: high-frequency TMS also improves depression, and depression reduces cognitive scores. Hence some of the improved cognitive scores in these studies may be from TMS’s effect on depression, not the Alzheimer’s Disease itself. Reassuringly, three studies (Cotelli, Turriziani, and Drumond) excluded patients with depression and still recorded positive results.
Another factor is the improvement that occurs naturally when repeating cognitive tests: i.e. patients get better with practice. Most relevant here are the cognitive exercises during TMS, since these will be performed dozens of times over the course of treatment. While the exercises are different from the tests before and after treatment, there may still be a crossover effect.
Important here are the studies without cognitive exercises, but these still rely on repeating the cognitive assessment after treatment. Even better is having a control group with cognitive exercises but sham TMS (Rabey and Turriziani). Here the results are less clear but still positive. Rabey (2013) specifically concluded that rTMS-cog is superior to cognitive exercises without TMS.
A key unanswered question is the effect of TMS on the long-term trajectory of Alzheimer’s Disease, which no existing treatment has demonstrated an ability to alter. For example, the most common medications, anticholinesterase inhibitors, only improve symptoms for around twelve months, which then return to the level of patients who never received treatment. The available studies have been too short to gauge whether TMS improves the overall trajectory, for example, whether TMS recipients are better off five years later.
The ideal treatment is one that produces a clear and permanent improvement to the natural history of the disease. For example, a medication which helps patients stop smoking will produce a definite increase in life expectancy. Yet applying this standard to Alzheimer’s Disease is misleading, given that dementia affects the final years of life and important to consider is not just years lived but the quality of those years. If a treatment did nothing to change the underlying disease but markedly reduced its symptoms for five years, that would be a massive benefit for Alzheimer’s patients: for example, perhaps the difference between spending one’s final years living independently or in nursing home.
Does this mean that patients who have improved with TMS will eventually return to the level of their untreated peers? Not necessary. Anticholinesterase inhibitors boost acetylcholine, which is a neurochemical at the end of an extraordinarily complex pathway of cellular interactions. While these medications can blunt and delay the full effect of dementia, there is evidence that TMS acts much further back in the chain, perhaps at the level of the disease itself.
How TMS works in Alzheimer’s Disease
Repetitive high-frequency TMS enhances cortical excitability, which involves the same kind of synaptic changes that are central to regular learning and memory. Part of this process is the expression of factors such as brain-derived neurotrophic factor (BDNF), which is reduced in Alzheimer’s Disease. Meanwhile animal studies have confirmed that rTMS increases BDNF levels .
rTMS also modulates the neurotransmitter GABA and changes a variety of inhibitory neuronal markers . These findings cohere with those showing that the APOE ε4 allele disrupts GABA inhibitory networks, which in turn influences aggregation of amyloid-beta .
TMS may also have effects through various neurochemicals, epigenetics and neural network dynamics . The evidence is complex and much remains to be understood, but research does reveal cellular effects of TMS in precisely the areas affected by Alzheimer’s Disease.
Given that TMS shows no effect on severe AD, the key area is the early stages when there is hope of altering the underlying damage to neurons.
One promising area comes from the pattern of altered neuronal excitability that marks an increased risk for Alzheimer’s . In vulnerable circuits, TMS may restore the disrupted excitatory / inhibitory balance that leads to amyloid-beta aggregation and associated neurotoxicity. Since this pattern of excitability appears before clinical symptoms, brain imaging might identify patients where TMS could attenuate the disease itself.
Most importantly, since TMS appears to work through identifiable structural changes (i.e. not by just boosting acetylcholine, like current medications), there is reason to believe that improvements will be more enduring.
So does TMS work for Alzheimer’s Disease? From the existing evidence, the answer is yes, provided that the treatment is early, and maintained. How long the benefits of TMS will last is yet to be investigated beyond a few months. However, with the evidence from cellular mechanisms, there is a strong possibility that TMS does alter the underlying disease mechanism, and therefore permanently alters its trajectory.
- Ahmed MA, Darwish ES, Khedr EM, El Serogy YM, Ali AM (2012) Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer’s dementia. J Neurol 259:83–92. 10.1007/s00415-011-6128-4
- Alcalá-Lozano R, Morelos-Santana E, Cortés-Sotres JF, Garza-Villarreal EA, Sosa-Ortiz AL, González-Olvera JJ (2018) Similar clinical improvement and maintenance after rTMS at 5 Hz using a simple vs. complex protocol in Alzheimer’s disease. Brain Stimul 11:625–627.
- Bentwich J, Dobronevsky E, Aichenbaum S, Shorer R, Peretz R, Khaigrekht M, Marton RG, Rabey JM (2011) Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease: a proof of concept study. J Neural Transm (Vienna)118:463–471. 10.1007/s00702-010-0578-1
- Buss SS, Fried PJ, Pascual-Leone A (2019) Therapeutic noninvasive brain stimulation in Alzheimer’s disease and related dementias. Curr Opin Neurol 32:292–304. 10.1097/WCO.0000000000000669
- Cotelli M, Manenti R, Cappa SF, Geroldi C, Zanetti O, Rossini PM, Miniussi C (2006) Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Arch Neurol63:1602–1604. 10.1001/archneur.63.11.1602
- Cotelli M, Manenti R, Cappa SF, Zanetti O, Miniussi C (2008) Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline. Eur J Neurol15:1286–1292. 10.1111/j.1468-1331.2008.02202.x
- Cotelli M, Calabria M, Manenti R, Rosini S, Zanetti O, Cappa SF, Miniussi C (2011) Improved language performance in Alzheimer disease following brain stimulation. J Neurol Neurosurg Psychiatry 82:794–797. 10.1136/jnnp.2009.197848
- Drumond Marra HL, Myczkowski ML, Maia Memória C, Arnaut D, Leite Ribeiro P, Sardinha Mansur CG, Lancelote Alberto R, Boura Bellini B, Alves Fernandes da Silva A, Tortella G, Ciampi de Andrade D, Teixeira MJ, Forlenza OV, Marcolin MA (2015) Transcranial magnetic stimulation to address mild cognitive impairment in the elderly: a randomized controlled study. Behav Neurol2015:287843. 10.1155/2015/287843
- Eliasova I, Anderkova L, Marecek R, Rektorova I (2014) Non-invasive brain stimulation of the right inferior frontal gyrus may improve attention in early Alzheimer’s disease: a pilot study. J Neurol Sci346:318–322. 10.1016/j.jns.2014.08.036
- Etiévant A, Manta S, Latapy C, Magno LA, Fecteau S, Beaulieu JM (2015) Repetitive transcranial magnetic stimulation induces long-lasting changes in protein expression and histone acetylation. Sci Rep 5:16873. 10.1038/srep16873
- Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349–1356. 10.1001/jama.278.16.1349
- Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Beckmann CF, Mackay CE (2009) Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 106:7209–7214. 10.1073/pnas.0811879106
- Friedman SD, Baker LD, Borson S, Jensen JE, Barsness SM, Craft S, Merriam GR, Otto RK, Novotny EJ, Vitiello MV (2013) Growth hormone-releasing hormone effects on brain γ-aminobutyric acid levels in mild cognitive impairment and healthy aging. JAMA Neurol 70:883–890. 10.1001/jamaneurol.2013.1425
- Heffernan AL, Chidgey C, Peng P, Masters CL, Roberts BR (2016) The neurobiology and age-related prevalence of the ε4 allele of apolipoprotein E in Alzheimer’s disease cohorts. J Mol Neurosci60:316–324. 10.1007/s12031-016-0804-x
- Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45:201–206. 10.1016/j.neuron.2004.12.033
- Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204–1222. 10.1016/j.cell.2012.02.040
- Huang Z, Tan T, Du Y, Chen L, Fu M, Yu Y, Zhang L, Song W, Dong Z (2017) Low-frequency repetitive transcranial magnetic stimulation ameliorates cognitive function and synaptic plasticity in APP23/PS45 mouse model of Alzheimer’s disease. Front Aging Neurosci 9:292.
- Jagust WJ, Mormino EC (2011) Lifespan brain activity, β-amyloid, and Alzheimer’s disease. Trends Cogn Sci 15:520–526. 10.1016/j.tics.2011.09.004
- Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M (2018) Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer’s disease. Neuroimage 169:302–311. 10.1016/j.neuroimage.2017.12.048
- Koch G, Martorana A, Caltagirone C (2019) Transcranial magnetic stimulation: emerging biomarkers and novel therapeutics in Alzheimer’s disease. Neurosci Lett. Advance online publication. Retrieved December 16, 2019. doi:10.1016/j.neulet.2019.134355. 10.1016/j.neulet.2019.134355
- Kumar S, Zomorrodi R, Ghazala Z, Goodman MS, Blumberger DM, Cheam A, Fischer C, Daskalakis ZJ, Mulsant BH, Pollock BG, Rajji TK (2017) Extent of dorsolateral prefrontal cortex plasticity and its association with working memory in patients with Alzheimer disease. JAMA Psychiatry 74:1266–1274. 10.1001/jamapsychiatry.2017.3292
- Lee J, Choi BH, Oh E, Sohn EH, Lee AY (2016) Treatment of Alzheimer’s disease with repetitive transcranial magnetic stimulation combined with cognitive training: a prospective, randomized, double-blind, placebo-controlled study. J Clin Neurol 12:57–64. 10.3988/jcn.2016.12.1.57
- Lenz M, Galanis C, Müller-Dahlhaus F, Opitz A, Wierenga CJ, Szabó G, Ziemann U, Deller T, Funke K, Vlachos A (2016) Repetitive magnetic stimulation induces plasticity of inhibitory synapses. Nat Commun 7:10020. 10.1038/ncomms10020
- Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, Halabisky B, Deng C, Mahley RW, Huang Y (2009) GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell 5:634–645. 10.1016/j.stem.2009.10.015
- Makowiecki K, Harvey AR, Sherrard RM, Rodger J (2014) Low-intensity repetitive transcranial magnetic stimulation improves abnormal visual cortical circuit topography and upregulates BDNF in mice. J Neurosci 34:10780–10792. 10.1523/JNEUROSCI.0723-14.2014
- Marron EM, Viejo-Sobera R, Quintana M, Redolar-Ripoll D, Rodríguez D, Garolera M (2018) Transcranial magnetic stimulation intervention in Alzheimer’s disease: a research proposal for a randomized controlled trial. BMC Res Notes 11:648. 10.1186/s13104-018-3757-z
- Nguyen JP, Suarez A, Kemoun G, Meignier M, Le Saout E, Damier P, Nizard J, Lefaucheur JP (2017) Repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease. Neurophysiol Clin 47:47–53. 10.1016/j.neucli.2017.01.001
- Padala PR, Padala KP, Lensing SY, Jackson AN, Hunter CR, Parkes CM, Dennis RA, Bopp MM, Caceda R, Mennemeier MS, Roberson PK, Sullivan DH (2018) Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: a double-blind, randomized, sham-controlled, cross-over pilot study. Psychiatry Res 261:312–318. 10.1016/j.psychres.2017.12.063
- Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818. 10.1038/nn.2583
- Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 7:695–702. 10.1016/0896-6273(91)90273-3
- Rabey JM, Dobronevsky E (2016) Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: clinical experience. J Neural Transm (Vienna) 123:1449–1455. 10.1007/s00702-016-1606-6
- Rabey JM, Dobronevsky E, Aichenbaum S, Gonen O, Marton RG, Khaigrekht M (2013) 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 Transm (Vienna) 120:813–819. 10.1007/s00702-012-0902-z
- Rutherford G, Lithgow B, Moussavi Z (2015) Short and long-term effects of rTMS treatment on Alzheimer’s disease at different stages: a pilot study. J Exp Neurosci 9:43–51. 10.4137/JEN.S24004
- Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766. 10.1152/physrev.2001.81.2.741
- Tang A, Thickbroom G, Rodger J (2017) Repetitive transcranial magnetic stimulation of the brain: mechanisms from animal and experimental models. Neuroscientist 23:82–94. 10.1177/1073858415618897
- Tong LM, Djukic B, Arnold C, Gillespie AK, Yoon SY, Wang MM, Zhang O, Knoferle J, Rubenstein JL, Alvarez-Buylla A, Huang Y (2014) Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation. J Neurosci34:9506–9515. 10.1523/JNEUROSCI.0693-14.2014
- Turriziani P, Smirni D, Zappalà G, Mangano GR, Oliveri M, Cipolotti L (2012) Enhancing memory performance with rTMS in healthy subjects and individuals with mild cognitive impairment: the role of the right dorsolateral prefrontal cortex. Front Hum Neurosci 6:62. 10.3389/fnhum.2012.00062
- Weiler M, Stieger KC, Long JM, Rapp PR. Transcranial Magnetic Stimulation in Alzheimer’s Disease: Are We Ready?. eNeuro. 2020;7(1):ENEURO.0235-19.2019. Published 2020 Jan 7. doi:10.1523/ENEURO.0235-19.2019
- Witte MM, Trzepacz P, Case M, Yu P, Hochstetler H, Quinlivan M, Sundell K, Henley D (2014) Association between clinical measures and florbetapir F18 PET neuroimaging in mild or moderate Alzheimer’s disease dementia. J Neuropsychiatry Clin Neurosci 26:214–220. 10.1176/appi.neuropsych.12120402
- Zhao J, Li Z, Cong Y, Zhang J, Tan M, Zhang H, Geng N, Li M, Yu W, Shan P (2017) Repetitive transcranial magnetic stimulation improves cognitive function of Alzheimer’s disease patients.Oncotarget 8:33864–33871. 10.18632/oncotarget.13060