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NCT Number: NCT07839650

Transcranial Alternating Current Stimulation (tACS) Combined With Cognitive Training in 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.

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Key information

Conditions

Transcranial Alternating Current Stimulation Alzheimer Dementia (AD) Alzheimer Disease Alzheimer Disease (AD) Brain Diseases Central Nervous System Diseases Cognitive Rehabilitation Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

IRCCS Istituto Centro San Giovanni Di Dio - Fatebenefratelli, Brescia, Italy

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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).

Treatment and study plan

Transcranial Alternating Current Stimulation

Device

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.

Sham transcranial alternating current stimulation

Device

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.

Individualized Computerized Memory Training

Behavioral

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.

Primary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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).

  9. 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.

  10. 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.

  11. 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.

Secondary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

Sponsors and collaborators

Lead sponsor

IRCCS Centro San Giovanni di Dio Fatebenefratelli

Other

Registry information

Official study title

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

Acronym: AD_tACSrehab

Important dates

Study start
2026
Primary completion
2031
Study completion
2032
First posted
Sep 24, 2026
Registry last updated
Sep 24, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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