SUMMARY
# Brain Connectivity-Targeted tACS Trial in Early AD
## Background and Rationale
Alzheimer's disease (AD) pathogenesis involves early network dysfunction preceding overt neurodegeneration, with resting-state fMRI revealing paradoxical hyperconnectivity in default mode network (DMN) regions during mild cognitive impairment (MCI) stages. This hyperconnectivity may facilitate trans-synaptic spread of pathological tau protein through anatomically connected brain regions, accelerating disease progres
METHODOLOGY NOTES
Phase 1 (Screening, Days -14 to 0): Screen participants meeting MCI criteria with evidence of AD pathology via CSF biomarkers or PET imaging. Conduct baseline assessments including resting-state fMRI (10-minute acquisition), structural MRI, comprehensive neuropsychological battery (ADAS-Cog, MoCA, episodic memory tests), and lumbar puncture for biomarkers. N=60 participants randomized 1:1 to active tACS versus sham. Phase 2 (Stimulation Protocol, Days 1-28): Deliver personalized tACS using individual fMRI connectivity maps to position electrodes over hyperconnected DMN regions. Apply 40 Hz stimulation at 2 mA peak-to-peak intensity for 20 minutes per session, 5 sessions weekly for 4 weeks. Sham group receives identical setup with imperceptible current (30 seconds ramp-up only). Monitor adverse events and tolerability daily. Phase 3 (Immediate Assessment, Days 29-35): Repeat baseline assessments including resting-state fMRI, cognitive testing, and biomarker sampling within one week post