Transcranial Alternating Current Stimulation (tACS) Combined With Cognitive Training in Alzheimer's Disease (AD_tACSrehab)

November 4, 2026 updated by: Prof. Barbara Borroni, IRCCS Centro San Giovanni di Dio Fatebenefratelli

Interventional Study to Evaluate the Effectiveness of Transcranial Alternating Current Stimulation (tACS) Combined With Cognitive Training on Cognitive Performance in Patients With Alzheimer's Disease

The aim of the study is to evaluate the clinical and biological efficacy, as well as predictors of efficacy, of a home-based intervention combining transcranial alternating current stimulation (tACS) with individualized computerized cognitive training in patients with mild Alzheimer's disease (AD).

In neurodegenerative diseases, including AD, neurodegeneration is accompanied by alterations in brain oscillatory activity. Restoration of these oscillations through neuronal entrainment has shown beneficial effects in animal models, while previous studies in patients with AD have demonstrated that gamma-frequency tACS applied over the precuneus is safe and well tolerated and is associated with improvements in cognitive performance and cholinergic function, as well as modulation of brain oscillatory activity. Cognitive rehabilitation may also improve memory performance in patients with mild AD. Based on this evidence, the present study investigates a multimodal approach combining gamma-tACS with individualized computerized memory training.

The study is a multicenter, randomized, placebo-controlled, double-blind trial involving 30 participants with mild AD. Participants will be randomly assigned to one of two groups: Group 1 will receive real gamma-tACS for 8 weeks (5 sessions/week, 60 minutes/session) combined with cognitive training (2 sessions/week, 30 minutes/session); Group 2 will receive sham tACS according to the same schedule, combined with the same cognitive training. tACS will be applied over the precuneus. Treatment will initially be performed in the hospital and will subsequently be administered at home under remote supervision by the study team.

Assessments will be performed at baseline (T00), after 8 weeks of treatment (T08), and at follow-up visits at 16 weeks (T16) and 24 weeks (T24) from baseline. At each time point, participants will undergo clinical and neuropsychological assessment, blood sampling, and transcranial magnetic stimulation (TMS). The occurrence of adverse events will be monitored throughout the duration of the study.

The main objectives of the study are: 1) to evaluate the short- and long-term effects of the combined intervention on cognitive performance; 2) to investigate intervention-induced changes in biological markers of neurodegeneration, inflammation, and synaptic function; 3) to evaluate the effects of the intervention on cholinergic transmission through the TMS short-latency afferent inhibition (SAI) measure; and 4) to investigate potential predictors of treatment efficacy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
30

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Milan, Italy
        • Not yet recruiting
        • IRCCS S. Maria Nascente - Fondazione Don Carlo Gnocchi
        • Contact:
          • Francesca Baglio, MD
          • Phone Number: +390240308951
    • Brescia
      • Brescia, Brescia, Italy, 25125
        • Recruiting
        • IRCCS Istituto Centro San Giovanni Di Dio - Fatebenefratelli
        • Principal Investigator:
          • Barbara Borroni, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Patients:

  • Male or female participants aged ≥18 years at the time of signing the informed consent form;
  • Clinical diagnosis of mild Alzheimer's disease (AD) according to current clinical criteria;
  • Availability of a caregiver who can assist the participant and who has successfully completed the required training for the use of the device at home.

Caregivers:

  • Male or female caregivers aged ≥18 years;
  • Compliance with participation in the in-hospital training;
  • Mini-Mental State Examination (MMSE) score >27/30.

Exclusion Criteria:

  • Age below that specified in the inclusion criteria;
  • Inability to understand;
  • Contraindications to tACS and TMS (e.g., presence of a cardiac pacemaker or metallic implants incompatible with electrical or magnetic fields, history of epilepsy, or current pregnancy, as assessed using the safety questionnaire).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Sham Comparator: Sham tACS
Behavioral: Individualized Computerized Memory Training

Participants will receive individualized computerized memory training for 8 weeks (2 sessions/week, 30 minutes/session) through synchronous telerehabilitation. The memory training will be individualized based on each participant's performance on the Face-Name Association Task (FNAT) and will use an errorless learning approach.

Device: Sham Transcranial Alternating Current Stimulation

40 at-home sessions (5 days/week for 8 weeks), each consisting of the application of sham tACS applied over the precuneus for a duration of 60 minutes each. The electrode placement will be identical to that used for real stimulation. However, the electrical current will be automatically interrupted approximately 5 seconds after the start of stimulation, making it impossible for the participant to distinguish between sham and real stimulation.
Experimental: Real tACS
Device: Transcranial Alternating Current Stimulation

40 at-home sessions (5 days/week for 8 weeks), each consisting of the application of tACS (real, 40 Hz) applied over the precuneus for a duration of 60 minutes each.

Behavioral: Individualized Computerized Memory Training

Participants will receive individualized computerized memory training for 8 weeks (2 sessions/week, 30 minutes/session) through synchronous telerehabilitation. The memory training will be individualized based on each participant's performance on the Face-Name Association Task (FNAT) and will use an errorless learning approach.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Mini-Mental State Examination (MMSE)
Time Frame: Change from baseline to week 24

The global cognitive functioning will be assessed by Mini-Mental State Examination (MMSE); MMSE scores range from 0 to 30, with higher scores indicating a more preserved cognition.
Change from baseline to week 24
Semantic Fluency Test
Time Frame: Change from baseline to week 8, 16, and 24

Lexical-semantic access and executive functioning will be evaluated by Semantic Fluency Test. Participant is asked to generate as many words as possible from a given category within a limited time (60 seconds); higher scores indicate better performance.
Change from baseline to week 8, 16, and 24
Trail Making Test (TMT - A, B)
Time Frame: Change from baseline to week 8, 16, and 24

Executive function will be assessed using the Trail Making Test, including Part A (visual attention and processing speed) and Part B (task switching and cognitive flexibility). Higher completion times reflect poorer performance.
Change from baseline to week 8, 16, and 24
Rey Auditory Verbal Learning Test (RAVLT)
Time Frame: Change from baseline to week 8, 16 and 24

Verbal memory will be assessed using the Rey Auditory Verbal Learning Test (RAVLT), including immediate recall (sum of trials), delayed recall after 15 minutes. Scores reflect the number of correctly recalled items.
Change from baseline to week 8, 16 and 24
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-13)
Time Frame: Change from baseline to week 8, 16 and 24

The ADAS-Cog-13 consists of 13 tasks assessing cognitive domains including memory, language, praxis, orientation, and attention. Total scores range from 0 to 85, with higher scores indicating greater cognitive impairment.
Change from baseline to week 8, 16 and 24
Face-Name Associative Memory Test (FNAT)
Time Frame: Change from baseline to week 8, 16 and 24

The Face-Name Associative Memory Test is used to assess the participant's associative memory and is composed of encoding and retrieval phases, with higher scores indicating better function.
Change from baseline to week 8, 16 and 24
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
Time Frame: Change from baseline to week 8, 16 and 24

ADCS-ADL evaluates activities of daily living. The scores range from 0-78 with lower scores indicating more severe functional impairment.
Change from baseline to week 8, 16 and 24
Neuropsychiatric Inventory (NPI)
Time Frame: Change from baseline to week 8, 16 and 24

Neuropsychiatric Inventory (NPI) is designed to be a structured clinical interview about neuropsychiatric and behavioral symptoms; the score ranges from 0 (no symptoms) to 144 (severe symptoms).
Change from baseline to week 8, 16 and 24
Clinical Dementia Rating scale - Sum of Boxes (CDR-SoB)
Time Frame: Change from baseline to week 8, 16 and 24

The Clinical Dementia Rating-Sum of Boxes (CDR-SB) assesses cognitive and functional impairment across six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Total scores range from 0 to 18, with higher scores indicating greater cognitive and functional impairment.
Change from baseline to week 8, 16 and 24
Clinical Dementia Rating scale - Global Score (CDR-GS)
Time Frame: Change from baseline to week 8, 16 and 24

The Clinical Dementia Rating Global Score (CDR-GS) assesses the overall severity of cognitive and functional impairment across six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Global scores range from 0 to 3, with higher scores indicating greater impairment.
Change from baseline to week 8, 16 and 24
Zarit Burden Interview (ZBI)
Time Frame: Change from baseline to week 8, 16, and 24

The Zarit Burden Interview (ZBI) assesses the perceived burden experienced by caregivers of individuals with dementia. It consists of 22 items rated on a 5-point scale. Total scores range from 0 to 88, with higher scores indicating greater caregiver burden.
Change from baseline to week 8, 16, and 24

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in SAI measurements
Time Frame: Change from baseline to week 8, 16, and 24

By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of gamma tACS on short latency afferent inhibition (SAI), which is a marker of cholinergic transmission. SAI is expressed as percent of the unconditioned motor evoked potential.
Change from baseline to week 8, 16, and 24
Change From Baseline in Biological Marker Concentrations
Time Frame: Change from baseline to week 8, 16, and 24

A venous blood draw will be performed at each timepoint. Samples will be processed for serum, plasma, and DNA extraction. Changes from baseline in biological marker concentrations, including plasma p-tau217, will be evaluated over time.
Change from baseline to week 8, 16, and 24
Demographic characteristics
Time Frame: Baseline

Demographic characteristics (age, gender, and level of education) will be evaluated as predictors of treatment efficacy and examined for associations with differential treatment response.
Baseline
Baseline Clinical Dementia Rating-Sum of Boxes (CDR-SB)
Time Frame: Baseline

The Clinical Dementia Rating-Sum of Boxes (CDR-SB) will be used to assess disease severity at baseline and evaluated as a predictor of treatment efficacy and examined for associations with differential treatment response. The CDR-SB assesses cognitive and functional impairment across six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Total scores range from 0 to 18, with higher scores indicating greater disease severity.
Baseline
Baseline Clinical Dementia Rating - Global Score (CDR-GS)
Time Frame: Baseline

The Clinical Dementia Rating - Global Score (CDR-GS) will be used to assess disease severity at baseline and evaluated as a predictor of treatment efficacy and examined for associations with differential treatment response. The CDR-SB assesses cognitive and functional impairment across six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Global scores range from 0 to 3, with higher scores indicating greater impairment.
Baseline
Level of Education and Occupational Attainment as Proxies of Cognitive Reserve
Time Frame: Baseline

Level of education and occupational attainment will be assessed at baseline as proxy measures of cognitive reserve and examined for associations with differential treatment response.
Baseline
Plasma Biomarker Profile
Time Frame: Baseline

The plasma biomarker profile will be evaluated as a predictor of treatment efficacy and examined for associations with differential treatment response.
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
IRCCS Centro San Giovanni di Dio Fatebenefratelli

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 16, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2031

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2032

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 14, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 21, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 24, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 5, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 4, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • AD_tACSrehab

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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