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

Not Applicable

Recruiting

• Conditions: Alzheimer Disease

• Registration Number: NCT07075770
• Lead Sponsor: I.R.C.C.S. Fondazione Santa Lucia

Brief 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. 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.

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.

Study Timeline

• Status Verified: 2025-01
• Study Start: 2025-01-01
• Study First Submitted: 2025-07-10
• Study First Submitted QC: 2025-07-10
• Last Update Submitted: 2025-07-10
• Study First Posted: 2025-07-20
• Last Update Posted: 2025-07-20
• Primary Completion: 2026-06-30
• Study Completion: 2026-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• 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
• 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

Exclusion Criteria

• 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:

  1. other primary degenerative dementia (Lewy body dementia, frontotemporal dementia, Huntington's disease, Creutzfeldt-Jakob disease, Down syndrome, etc.);
  2. other neurodegenerative conditions (Parkinson's disease, amyotrophic lateral sclerosis, etc.);
  3. orthostatic hypotension and autonomic disorders
  4. cerebrovascular disease (major infarction, a strategic infarction or multiple lacunar infarctions, extensive white matter lesions > one quarter of total white matter);
  5. other central nervous system diseases (severe traumatic brain injury, tumors, subdural hematoma, or other space-occupying processes, etc.);
  6. seizure disorder.
  7. 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:

  1. Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, severe language difficulties, etc.);
  2. Opioid-containing analgesics
  3. 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;
  4. Any condition that, in the investigator's judgment, makes the patient unsuitable for inclusion

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change in the Clinical Dementia Rating scale Sum of Boxes (CDR-SoB) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	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.

Secondary Outcome Measures

Name	Time	Method
Change in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	The ADCS-ADL includes 23 items that were derived from a larger set of items describing performance of activities of daily living.
Change in the Alzheimer Disease Assessment Cognitive Scale (ADAS-Cog) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	The ADAS-Cog assesses the level of cognitive function in Alzheimer's Disease. The ADAS-Cog consists of items from the following areas chosen for their sensitivity to Alzheimer's Disease: language; memory; praxis executive functions and orientation.
Change in the Neuropsychiatric Personal Inventory (NPI) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	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.
Change in the Mini-Mental State Examination (MMSE) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	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.
Change in the Montreal Overall Cognitive Assessment (MoCA) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	The MoCA is a brief screening tool for mild cognitive impairment, scored from 0 to 30, with higher scores indicating better cognitive functions.
Change in Face-Name Association Task (FNAT) score.	Baseline (week 0); post-intensive phase (week 2); mid-treatment evaluation (week 12); post-treatment (week 24).	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.
Change in Apathy Motivation index (AMI) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	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.
Change in the Frontal Assessment Battery (FAB) score.	Baseline (week 0); mid-treatment evaluation (week 12); post-treatment (week 24).	The FAB is a brief battery of six neuropsychological tasks designed to assess frontal lobe function.

Trial Locations

Locations (2)

I.R.C.C.S. Centro Neurolesi Bonino Pulejo; 🇮🇹 Messina, Sicily, Italy

IRCCS Santa Lucia Foundation; 🇮🇹 Rome, Italy