Gamma-frequency transcranial alternating current stimulation (tACS) has emerged as a promising noninvasive neuromodulatory approach for Alzheimer's Disease (AD), leveraging on the role of 40Hz oscillatory dysfunction in amyloid- and tau-related pathology (Iaccarino et al., 2016; Jafari et al., 2020). Evaluate feasibility, safety, and multimodal response patterns of multisession 40 Hz gamma-tACS in MCI-AD, distinguishing the role of gamma entrainment and blood biomarkers in shaping individual cognitive trajectories.

98% adherence (59/60 sessions). Side effects minimal and transient; no seizures, epileptiform activity, or clinically significant adverse events. RBANS: g = 1.82 (T1), g = 0.65 (T2). Associative memory(ItFNAT-DTR): g = 1.32 (T2). Autonomypreserved. Increased memory complaints (PRMQ) likely reflect enhanced metacognitive awareness rather than true functional decline. Plasma biomarkers largely stable. Progressive Aβ42/Aβ40 ratio reduction at T1 (g = −0.58) and T2 (g = −2.10), driven by rising Aβ40. Auditory 40 Hz entrainment: temporal g = 3.48, central g = 1.82 (both T2), robust and consistent across all completers.

Multi-session gamma-tACS is safe, feasible, and effective in MCI-AD, with sustained cognitive and electrophysiological effects.

• Objective cognitive performance improved substantially post-treatment and was maintained at 3-month follow-up, confirming a genuine and durable treatment effect

• Cognitive gains closely parallel neural entrainment improvements, identifying gamma entrainment as the most sensitive marker of treatment response

• Consistent 40Hz entrainment, with evidence of individual neuroplastic reorganization, supports gamma-tACS as a genuine neuromodulatory tool

Gamma neuromodulation provides a direct, noninvasive, and cost-effective candidate for personalized treatments in prodromal AD.