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Alzheimer DiseaseCMES_ADNCT07075770

Novel Personalized Non Invasive Combined Magnetic and Electrical Stimulation of the DMN in Mild AD Patients

A study testing Combined iTBS-tACS in people with Alzheimer Disease, run by I.R.C.C.S. Fondazione Santa Lucia at 2 sites in Italy.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

Alzheimer's disease (AD) is increasingly recognized as a disorder marked by early synaptic dysfunction and disrupted brain network connectivity, beyond the traditional focus on amyloid pathology. Synaptic plasticity (crucial for learning and memory) is compromised in AD and represents a promising therapeutic target. Read more about this study

Who is it for?
Ages 50 to 85 years
Conditions the study is for
Alzheimer Disease
What is being tested?
Combined iTBS-tACS
Type of treatment
Medical device
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
60 participants
Where
2 sitesItaly
Study dates
1 Jan 2025to 31 Aug 2027
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with a diagnosis of AD according to IWG criteria
  • 20 > MMSE < 28
  • Patients with CSF specific biomarker profile or with a positive Amyloid Pet Scan consistent with the presence of amyloid pathology
  • Global Clinical Dementia Rating (CDR) ≤1
  • Previous decline in cognition for more than six months as documented in patient medical records
  • A caregiver available and living in the same household or interacting with the patient and available
Show all 11Show fewer
  • Patients living at home or nursing home setting without continuous nursing care
  • General health status acceptable for a participation in a 6-month clinical trial
  • Stable pharmacological treatment for at least one month prior to screening
  • No regular intake of prohibited medications.
  • Signed informed consent by the patient. If there are any doubts that the patient is mentally capable of giving informed consent, the patient will be examined and verified to be mentally capable by an independent physician/ neurologist, prior to the initiation of any study specific procedure. Signed consent of the caregiver

Who cannot join

  • Failure to undergo screening or baseline exams
  • Hospitalization or change in chronic concomitant medications one month before the screening or during the screening period
  • Clinical, laboratory, or neuroimaging results consistent with:
  • other primary degenerative dementia (Lewy body dementia, frontotemporal dementia, Huntington's disease, Creutzfeldt-Jakob disease, Down syndrome, etc.);
  • other neurodegenerative conditions (Parkinson's disease, amyotrophic lateral sclerosis, etc.);
  • orthostatic hypotension and autonomic disorders
Show all 16Show fewer
  • cerebrovascular disease (major infarction, a strategic infarction or multiple lacunar infarctions, extensive white matter lesions > one quarter of total white matter);
  • other central nervous system diseases (severe traumatic brain injury, tumors, subdural hematoma, or other space-occupying processes, etc.);
  • seizure disorder.
  • Other infectious, metabolic, or systemic diseases affecting the central nervous system (syphilis, existing hypothyroidism, current vitamin B12 or folate deficiency, serum electrolytes outside normal limits, juvenile diabetes, etc.).
  • A current DSM-V diagnosis of major depression, schizophrenia, or bipolar disorder.
  • Clinically significant, advanced, or unstable disease that may interfere with primary or secondary variable assessments and may affect the assessment of the patient's clinical or mental state, or expose the patient to special risk, such as:
  • Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, severe language difficulties, etc.);
  • Opioid-containing analgesics
  • Suspected or known drug or alcohol abuse, i.e., more than about 60 g of alcohol (about 1 liter of beer or 500 ml of wine) per day, indicated by a high mean corpuscular volume (MCV) above the normal value at screening;
  • Any condition that, in the investigator's judgment, makes the patient unsuitable for inclusion

Trial locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Giacomo Koch, Prof contact

+390651501181

g.koch@hsantlucia.it

Italy2 sites, 2 recruiting

  • I.R.C.C.S. Centro Neurolesi Bonino Pulejo

    Messina, Sicily, 98124

    Rosaria De Luca, PhD, rosaria.deluca@irccsme.it

    Not yet recruiting

  • IRCCS Santa Lucia Foundation

    Rome, Italy, 00179

    Giacomo Koch, Prof, +390651501181, g.koch@hsantalucia.it

    Sonia Bonnì, PhD

    Recruiting

Other trials in Italy

About this study

Official title: Novel Personalized Non Invasive Combined Magnetic and Electrical Stimulation of the Default Mode Network in Mild AD Patients (CMES-AD)

Alzheimer's disease (AD) is increasingly recognized as a disorder marked by early synaptic dysfunction and disrupted brain network connectivity, beyond the traditional focus on amyloid pathology. Synaptic plasticity (crucial for learning and memory) is compromised in AD and represents a promising therapeutic target. In particular, alterations in the Default Mode Network (DMN), especially in regions like the precuneus, suggest that restoring connectivity and enhancing plasticity may improve cognitive outcomes. This project proposes a novel, precision-delivered non-invasive brain stimulation protocol that combines repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) over the DMN. The intervention will be evaluated through cognitive testing, blood-based biomarkers, MRI and TMS-EEG, alongside immersive virtual environments to assess sensorimotor and cognitive function. This approach aims to test neuromodulation strategies capable of slowing neurodegeneration and supporting early detection and rehabilitation in AD.

Read the detailed description

Patients will be screened at trial sites for determination of eligibility to enter the study on the basis of diagnostic evaluations, according to current diagnostic criteria for probable AD, and safety assessments (vital sign complete physical and neurological examinations). The efficacy assessments (cognitive/behavioral evaluations) will be performed at Baseline before starting treatment and repeated on- treatment at Weeks 0, 12 and 24. Plasma biomarkers will be collected at baseline and at Week 12 and 24. Visit windows are ±7 days for all the scheduled visits. In case a visit is performed outside its window, subsequent visits will be performed in keeping with the original visit schedule. At each in-clinic visit (or upon early termination), AEs will be recorded, at screening, baseline, Week 12 and 24 vital signs measured, and physical and neurological examination performed.

Being tested
Combined iTBS-tACS, iTBS-sham tACS, sham iTBS- sham tACS
Keywords
Non Invasive Brain Stimulation, Transcranial Magnetic Stimulation, Intermittent Theta Burst Stimulation, Transcranial Electrical Stimulation, Transcranial Alternating Current Stimulation, Default Mode Network
Medical subject headings
Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Combined iTBS-tACSDevice

    The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds. iTBS and tACS will be synchronized using a BrainTrigger and SIGNAL Software so that both stimulations will start simultaneously

  • iTBS-sham tACSDevice

    The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds.

    For the tACS sham condition, the electric current will not be applied, but there will be a 2 s 1 mA ramp up and 2 s 1 mA ramp down, to give the participant real stimulation feelings.

  • sham iTBS- sham tACSDevice

    The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds.

    For the iTBS sham condition, stimulation was delivered with the coil angled at 90°, with only the edge of the coil resting on the scalp..

    For the tACS sham condition, the electric current will not be applied, but there will be a 2 s 1 mA ramp up and 2 s 1 mA ramp down, to give the participant real stimulation feelings.

Study groups in NCT07075770
Study groupRoleWhat they receive
combined iTBS-tACSExperimental32 sessions of combined iTBS-tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
Receives: Device: Combined iTBS-tACS
iTBS-sham tACSActive comparator32 sessions of combined iTBS-sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
Receives: Device: iTBS-sham tACS
sham iTBS- sham tACSPlacebo comparator32 sessions of sham iTBS- sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
Receives: Device: sham iTBS- sham tACS

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. integrated Alzheimer Disease Rating Scale (iADRS)

    The iADRS is an integrated assessment of cognition and daily function from the 13-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog13) and Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL), measuring global disease severity across the Alzheimer disease continuum as a single summary score. The iADRS is validated and captures clinical progression from MCI due to Alzheimer disease through moderate dementia due to Alzheimer disease, and treatment effects have been demonstrated across MCI and Alzheimer disease with mild dementia. The possible scores on the iADRS range from 0 to 144 (lower scores indicate greater impairment).

    Measured: Change from baseline to the end of treatment at week 24.

Secondary outcomes (10)

  1. Change in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score.

    The ADCS-ADL includes 23 items that were derived from a larger set of items describing performance of activities of daily living.

    Measured: Change from baseline to the end of treatment at week 24.

  2. Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL).

    A standardized clinical scale used to assess an individual's ability to perform complex daily tasks.

    Measured: Change from baseline to week 24.

  3. Change in the Clinical Dementia Rating scale Sum of Boxes (CDR-SoB) score.

    The CDR-SoB is a 5-point scale used to characterize six domains of cognitive and functional performance in AD and related dementias: Memory, Orientation, Judgment \& Problem Solving, Community Affairs, Home \& Hobbies, and Personal Care.

    Measured: Change from baseline to the end of treatment at week 24.

  4. Change in the Alzheimer Disease Assessment Cognitive Scale (ADAS-Cog13) score.

    The ADAS-Cog13 assesses the level of cognitive function in Alzheimer's Disease. The ADAS-Cog13 consists of items from the following areas chosen for their sensitivity to Alzheimer's Disease: language; memory; praxis executive functions and orientation.

    Measured: Change from baseline to the end of treatment at week 24.

  5. Change in the Neuropsychiatric Personal Inventory (NPI) score.

    The NPI scale assesses behavioral disturbances in dementia. The NPI is a reliable and valid scale measuring the following behavioral areas: delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behavior, night time behaviors, and eating disorders. The score range is from 0 to 144 with the higher score meaning more severe behavioural disturbances.

    Measured: Change from baseline to the end of treatment at week 24.

  6. Change in the Mini-Mental State Examination (MMSE) score.

    The MMSE is a brief, widely used valid, and reliable assessment of cognitive impairment. This 30-point questionnaire is used to screen and estimate the severity of cognitive impairment in addition to being used to follow the course of cognitive change over time. The test assesses orientation, attention and calculation, recall, language, repetition, and ability to follow complex commands. The score range is from 0 to 30, with lower score meaning greater cognitive impairment.

    Measured: Change from baseline to the end of treatment at week 24.

  7. Change in the Montreal Overall Cognitive Assessment (MoCA) score.

    The MoCA is a brief screening tool for mild cognitive impairment, scored from 0 to 30, with higher scores indicating better cognitive functions.

    Measured: Change from baseline to the end of treatment at week 24.

  8. Change in Face-Name Association Task (FNAT) score.

    The FNAT is a cross-modal memory test where participants learn and recall pairs of unfamiliar faces and common first names. In this study, only face-name pairs were used (no occupations). The score reflects the number of correctly recalled names, with higher scores indicating better associative memory.

    Measured: Change from baseline to the end of treatment at week 24.

  9. Change in Apathy Motivation index (AMI) score.

    The AMI scores range from 0 to 4 for each item, with higher scores indicating greater levels of apathy. The total score is calculated by averaging item scores across its subscales.

    Measured: Change from baseline to the end of treatment at week 24.

  10. Change in the Frontal Assessment Battery (FAB) score.

    The FAB is a brief battery of six neuropsychological tasks designed to assess frontal lobe function.

    Measured: Change from baseline to the end of treatment at week 24.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Jul 2025
  2. Study start1 Jan 2025
  3. Primary completion30 Jun 2027 (estimated)
  4. Study completion31 Aug 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Three arms randomized sham-controlled trial
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07075770
Sponsor's protocol ID
PNRR-MCNT2-2023-12377518
Acronym
CMES_AD
Status last verified
Jan 2025
First submitted
10 Jul 2025
Last updated
13 Jan 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Chou HY, Chen SC, Yen TH, Han HM. Effect of a Virtual Reality-Based Exercise Program on Fatigue in Hospitalized Taiwanese End-Stage Renal Disease Patients Undergoing Hemodialysis. Clin Nurs Res. 2020 Jul;29(6):368-374. doi: 10.1177/1054773818788511. Epub 2018 Jul 15.

    PubMed 30009636

  • Blennow K, Zetterberg H. Biomarkers for Alzheimer's disease: current status and prospects for the future. J Intern Med. 2018 Dec;284(6):643-663. doi: 10.1111/joim.12816. Epub 2018 Aug 19.

    PubMed 30051512

  • Fox MD, Halko MA, Eldaief MC, Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). Neuroimage. 2012 Oct 1;62(4):2232-43. doi: 10.1016/j.neuroimage.2012.03.035. Epub 2012 Mar 19.

    PubMed 22465297

  • Gili T, Cercignani M, Serra L, Perri R, Giove F, Maraviglia B, Caltagirone C, Bozzali M. Regional brain atrophy and functional disconnection across Alzheimer's disease evolution. J Neurol Neurosurg Psychiatry. 2011 Jan;82(1):58-66. doi: 10.1136/jnnp.2009.199935. Epub 2010 Jul 16.

    PubMed 20639384

  • Koch G, Casula EP, Bonni S, Borghi I, Assogna M, Minei M, Pellicciari MC, Motta C, D'Acunto A, Porrazzini F, Maiella M, Ferrari C, Caltagirone C, Santarnecchi E, Bozzali M, Martorana A. Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial. Brain. 2022 Nov 21;145(11):3776-3786. doi: 10.1093/brain/awac285.

    PubMed 36281767

  • 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. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 Dec 19.

    PubMed 29277405

  • Hu Y, Kirmess KM, Meyer MR, Rabinovici GD, Gatsonis C, Siegel BA, Whitmer RA, Apgar C, Hanna L, Kanekiyo M, Kaplow J, Koyama A, Verbel D, Holubasch MS, Knapik SS, Connor J, Contois JH, Jackson EN, Harpstrite SE, Bateman RJ, Holtzman DM, Verghese PB, Fogelman I, Braunstein JB, Yarasheski KE, West T. Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment. JAMA Netw Open. 2022 Apr 1;5(4):e228392. doi: 10.1001/jamanetworkopen.2022.8392.

    PubMed 35446396

  • Bonni S, Esposito R, Mencarelli L, Di Lorenzo F, Ricci F, Di Iulio F, Savastano E, Candeo F, De Masi F, Coletta A, Vinci AC, Ferraresi M, Mancini M, Casula EP, Borghi I, Spampinato DA, Maiella M, Cinnera AM, Assogna M, Bruno M, Nocilli M, Ferrara M, Russo M, Tagliamonte NL, Ferrari C, Bertino S, Calabro RS, Maggio MG, De Luca R, Burrascano R, Gjonaj E, Mirabile A, De Pasquale P, d'Avella A, Quartarone A, Koch G. Personalized non-invasive combined magnetic and electrical stimulation of the default mode network in mild AD patients (CMES-AD): a multicentric randomized sham-controlled trial protocol. Alzheimers Res Ther. 2026 Jul 21. doi: 10.1186/s13195-026-02145-x. Online ahead of print.

    PubMed 42482244

Questions about this trial

What is this clinical trial studying?

A study testing Combined iTBS-tACS in people with Alzheimer Disease, run by I.R.C.C.S. Fondazione Santa Lucia at 2 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 13 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Giacomo Koch, Prof (+390651501181, g.koch@hsantlucia.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

integrated Alzheimer Disease Rating Scale (iADRS) (time frame: Change from baseline to the end of treatment at week 24.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07075770, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2026.

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