An interventional study of Combined iTBS-tACS and iTBS-sham tACS in Alzheimer Disease, sponsored by I.R.C.C.S. Fondazione Santa Lucia. Recruiting at 2 sites in Italy. Open to participants aged 50 Years to 85 Years. Per ClinicalTrials.gov, last updated 2026-01-13.
Sponsored by I.R.C.C.S. Fondazione Santa Lucia · Not applicable, Interventional, and Treatment
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.
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.
3,965 studies on the registry are indexed under Alzheimer Disease; 926 are open to participants now.
This study's planned enrollment of 60 is below the median of 70 across 3,019 interventional studies indexed under Alzheimer Disease.
Browse Alzheimer Disease studies →I.R.C.C.S. Fondazione Santa Lucia is the lead sponsor of 56 studies on the registry; 16 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Clinical, laboratory, or neuroimaging results consistent with:
, 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:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
MMSE and MoCA
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
DSM diagnostic criteria
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
32 sessions of combined iTBS-tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
Device: Combined iTBS-tACS
32 sessions of combined iTBS-sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
Device: iTBS-sham tACS
32 sessions of sham iTBS- sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
Device: sham iTBS- sham tACS
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
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.
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.
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).
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
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.
Time frame: Change from baseline to the end of treatment at week 24.
Change in the Frontal Assessment Battery (FAB) score.
The FAB is a brief battery of six neuropsychological tasks designed to assess frontal lobe function.
Time frame: Change from baseline to the end of treatment at week 24.
Change in cortical activity
From TMS-EEG recording it is possible to analyze oscillatory activity of the stimulated brain area. Monitoring the frequency band during time after TMS-pulse we calculate Time-frequency Wavelets and from there the TMS-related spectral perturbation (TRSP) as output of the frequency bands (Delta, Theta, Alpha, Beta, Gamma) expressed.
Time frame: Change from baseline to the end of treatment at week 24.
Change in the cortical connectivity
Monitoring how TMS-induced EEG activity spreads from the stimulated area to the other areas, it is possible to assess the effective connectivity that area has with a widespread of network connected. So we calculate the source reconstruction, coherence between different areas and other connectivity indexes in the cortical oscillatory domain, i.e. Phase-locking Value (PLV) and Phase-amplitude coupling (PAC).
Time frame: Change from baseline to the end of treatment at week 24.
Change in Virtual Reality task performance.
The motor task will be assessed using the Gait Real-time Analysis Interactive Lab (GRAIL) system and a certified VR headset, measuring kinematic variables (walking speed in m/s and joint trajectories in degrees) and performance metrics (number of targets hit and reaction time in ms) under dual-task conditions.
Time frame: Change from baseline to the end of treatment at week 24.
Changes in the blood-based biomarkers
Plasma concentrations of Aβ42, Aβ40, P-tau217, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), neurogranin, SNAP25 will be quantified using Single Molecule Array (Simoa) assays and reported in pg/mL.
Time frame: Change from baseline to the end of treatment at week 24.
Changes on MRI markers of regional gray matter atrophy and functional connectivity
Will measure changes in brain structure, tissue integrity, and atrophy, as well as changes in brain activity and blood flow using resting-state functional MRI (fRMI) and arterial spin labeling (ASL).
Time frame: Change from baseline to the end of treatment at week 24.
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I.R.C.C.S. Fondazione Santa Lucia