Transcranial Alternating Current Stimulation for Patients With Mild Alzheimer's Disease II (TRANSFORM-AD II)

Official title

The Effects of TRanscranial AlterNating Current Stimulation FOR Patients With Mild Alzheimer's Disease II (TRANSFORM-AD II Study): A Randomized Controlled Clinical Trial

Overview

The goal of this study is to explore the efficacy and safety of transcranial alternating current stimulation (tACS) in patients with amnestic mild cognitive impairment due to Alzheimer's disease (AD-aMCI) and patients with mild Alzheimer's disease dementia (AD-MD). The study will recruit 160 individuals with mild cognitive impairment with evidence of amyloid plaques in the brain through Positron Emission Tomography (PET) imaging. Participants will undergo baseline cognitive assessment, structural and functional MRI characterization, PiB-PET, and EEG measurement. The participants will be randomized to either a tACS group or a sham stimulation group. At the end of the intervention, all subjects will repeat the baseline assessments.

Detailed description

Background In our previous study, we applied 40 Hz transcranial alternating current stimulation (tACS) to patients with mild Alzheimer's disease (AD), and the results demonstrated significant improvements in cognitive function. Building upon these findings, the present study applies a combined high-gamma (77.5 Hz) and low-gamma (40 Hz) tACS protocol to target patients with amnestic mild cognitive impairment due to Alzheimer's disease (AD-aMCI) and those with mild Alzheimer's disease dementia (AD-MD). This dual-frequency stimulation aims to enhance cognitive performance through synergistic gamma-band modulation and to explore its underlying therapeutic mechanisms.

Methods The TRANSFORM-AD II trial is a double-blind, randomized controlled study that will enroll 160 participants diagnosed with AD-aMCI or AD-MD. Eligible participants must meet at least one of the following criteria: positive amyloid positron emission tomography (PET), decreased cerebrospinal fluid (CSF) amyloid-β levels, or elevated plasma phosphorylated tau 217 (p-Tau217) levels. Participants will be randomly assigned to either the active stimulation group (77.5 Hz + 40 Hz tACS) or the sham stimulation group. Both groups will receive 60 one-hour sessions over an 8-week period. Outcome measures will be assessed at baseline and immediately after the intervention.

The primary outcome is global cognitive function, measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13).

Secondary outcomes include changes in other neuropsychological test scores, multimodal magnetic resonance imaging (MRI) metrics, and resting-state as well as task-related electroencephalography (EEG) indicators.

Results This trial is currently ongoing, with recruitment expected to be completed by June 2026.

Conclusion This study will evaluate the efficacy and safety of combined 77.5 Hz and 40 Hz tACS in patients with AD-related aMCI and mild AD dementia. Furthermore, it will investigate potential therapeutic mechanisms using multimodal MRI to assess brain structure and function, and EEG to characterize both resting-state and task-related neural activity patterns.

Interventions

• Device sham stimulation
  Electrodes will also be placed on the patient's forehead and behind both ears. The sham stimulator is identical in appearance to the true stimulator. Neither participants nor operators can distinguish whether the stimulator is real based on its appearance or the patient's sensations. However, when the device is activated, no current flows through the electrodes. Participants in this group will receive sham stimulation with 60 one-hour sessions within 8 weeks.
• Device transcranial alternating current stimulation
  The alternating current is delivered through medical-grade conductive electrode pads manufactured specifically for Nexalin technology. The electrode pads are placed on the forehead and behind both ears, and are connected to the Nexalin device with thin cables. The intervention will be conducted with a tACS device: 50 minutes of high-gamma frequency (77.5 Hz) combined with 10 minutes of low-gamma frequency (40 Hz), with a peak-to-peak amplitude of 15 mA. A total of 60 one-hour sessions will be co

Primary outcome measures

• Change in Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog, 13-items version). [Time frame: up to 8 weeks (end of intervention)]

Secondary outcome measures (12)

• Change in MRI brain connectivity [Time frame: up to 8 weeks (end of intervention)]
• Temporal lobe cross-frequency coupling dynamics and intervention effects [Time frame: Up to 8 weeks (end of intervention)]
• Changes in brain volume and brain function [Time frame: up to 8 weeks (end of intervention)]
• Change in Mini-mental State Examination [Time frame: up to 8 weeks (end of intervention)]
• Change in Montreal Cognitive Assessment [Time frame: up to 8 weeks (end of intervention)]
• Change in Clinical Dementia Rating Scale sum of the boxes [Time frame: up to 8 weeks (end of intervention)]
• Change in memory function [Time frame: up to 8 weeks (end of intervention)]
• Change in Digit span forward [Time frame: up to 8 weeks (end of intervention)]
• Change in Digit span backward [Time frame: up to 8 weeks (end of intervention)]
• Change in Trail Making Test [Time frame: up to 8 weeks (end of intervention)]
• Change in Boston Naming Test [Time frame: up to 8 weeks (end of intervention)]
• Change in Neuropsychiatric Inventory (NPI) [Time frame: up to 8 weeks (end of intervention)]

Eligibility criteria

Inclusion criteria

• Patients aged 50-90 years, either inpatients or outpatients;
• Meeting the NIA-AA clinical diagnostic criteria established by the 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) group for AD-related amnestic mild cognitive impairment (a-MCI) or AD-related mild dementia;
• Neuropsychological evaluation with MMSE score of 18-26 and CDR score of 0.5 or 1;
• Positive amyloid PET, or decreased amyloid levels in cerebrospinal fluid, or elevated serum phosphorylated Tau217 protein;
• Able to communicate proficiently in Chinese (non-illiterate);
• If currently receiving cholinesterase inhibitor treatment (such as donepezil or rivastigmine), the current treatment dose must be stable (i.e., fixed dose for at least 6 consecutive weeks), with no planned dose adjustments during the study observation period;
• Signed informed consent form.

Exclusion criteria

• Sudden onset;
• Early focal neurological manifestations or extrapyramidal manifestations;
• Systemic diseases that may cause cognitive impairment (such as liver or kidney insufficiency, endocrine diseases, or vitamin deficiency), or neurological diseases such as brain trauma, epilepsy, encephalitis, or normal pressure hydrocephalus;
• Meeting DSM-IV criteria for depression or schizophrenia;
• Ongoing drug treatments that may affect baseline or follow-up assessments;
• Contraindications for MRI or neurophysiological examinations, such as cardiac pacemakers, cardiac defibrillators, implanted electronic systems, vascular clips, mechanical heart valves, or cochlear implants;
• Cranial MRI showing ischemic lesions meeting NINCDS-AIREN criteria.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Xuanwu Hospital, Capital Medical University — Beijing

Identifiers

NCT: NCT07230158 · 2023173

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗