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 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
Failure to undergo screening or baseline exams
Hospitalization or change in chronic concomitant medications one month before the screening or during the screening period
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.);
Parallel
Combined iTBS-tACS
DeviceThe 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 tACS
DeviceThe 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 tACS
DeviceThe 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).
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.
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.
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.
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.
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.
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).
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.
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.
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I.R.C.C.S. Fondazione Santa Lucia
Lead sponsor
IRCCS Centro Neurolesi Bonino Pulejo
Collaborator
