Transcranial Alternating Current Stimulation, Alzheimer Disease (AD), Alzheimer Dementia (AD), Cognitive Rehabilitation
Conditions
Brief summary
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.
Interventions
DEVICETranscranial 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.
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.
BEHAVIORALIndividualized 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.
Sponsors
IRCCS Centro San Giovanni di Dio Fatebenefratelli
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mini-Mental State Examination (MMSE) | 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. |
| Semantic Fluency Test | 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. |
| Trail Making Test (TMT - A, B) | 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. |
| Rey Auditory Verbal Learning Test (RAVLT) | 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. |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-13) | 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. |
| Face-Name Associative Memory Test (FNAT) | 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. |
| Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | 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. |
| Neuropsychiatric Inventory (NPI) | 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). |
| Clinical Dementia Rating scale - Sum of Boxes (CDR-SoB) | 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. |
| Clinical Dementia Rating scale - Global Score (CDR-GS) | 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. |
| Zarit Burden Interview (ZBI) | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in SAI measurements | 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 in Biological Marker Concentrations | 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. |
| Demographic characteristics | 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 Clinical Dementia Rating-Sum of Boxes (CDR-SB) | 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 Clinical Dementia Rating - Global Score (CDR-GS) | 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. |
| Level of Education and Occupational Attainment as Proxies of Cognitive Reserve | 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. |
| Plasma Biomarker Profile | Baseline | The plasma biomarker profile will be evaluated as a predictor of treatment efficacy and examined for associations with differential treatment response. |
Countries
Italy
Outcome results
None listed