Restoration of Gamma Center Frequency via Personalized Entrainment Marks Cognitive Preservation in Early Alzheimer's Disease

BackgroundGamma entrainment shows promise for Alzheimers disease (AD) treatment in preclinical models, but human trials have yielded heterogeneous results. We hypothesized that the clinical efficacy of gamma entrainment depends on individual neurophysiological receptivity, specifically the capacity for neural circuit plasticity. MethodsIn this open-label pilot study, we screened 37 individuals and enrolled 16 participants with early AD (CDR 0.5-1.0, amyloid-positive) who completed 12 weeks of home-based flickering light stimulation at individually optimized gamma frequencies (32-40 Hz). Pre- and post-intervention assessments included 64-channel EEG recordings and MMSE. ResultsParticipants demonstrated dichotomous neurophysiological responses: 43.8% showed CF increase (ICF+) while 56.3% showed no change/decrease (ICF-). CF restoration was significantly associated with cognitive preservation (r=0.52, p=0.039). Notably, future responders exhibited distinct baseline signatures of "neural reserve," characterized by higher temporal gamma power (Cohens d=0.70-0.92) and stronger frontotemporal connectivity (Cohens d=1.11-1.47). Almost 30% of screened candidates failed to show baseline entrainment, highlighting a distinct "non-responsive" biological subtype. DiscussionCF restoration following personalized gamma entrainment identifies a neurophysiological subtype capable of meaningful plasticity. Rather than a universal remedy, gamma entrainment appears to act on specific neural substrates preserved in a subset of patients. These findings suggest that baseline electrophysiological profiling could unlock gamma entrainments therapeutic potential by stratifying likely responders for precision neuromodulation.