Divergent Cognitive Trajectories by Gamma Center Frequency Plasticity After Personalized Gamma Entrainment in Early Alzheimer Disease: A Dechallenge Analysis

BackgroundNon-invasive gamma entrainment using sensory stimulation (GENUS) is being investigated as a therapy for Alzheimer disease (AD), but the clinical course of participants who fail to show gamma center frequency plasticity remains unclear. We therefore examined whether cognitive decline observed during personalized GENUS was attenuated after cessation in participants stratified post hoc by CF change. MethodsThis case series was derived from an open-label proof-of-concept trial with extended follow-up (mean 26.3 months). Sixteen participants with amyloid-positive early AD completed 12 weeks of home-based daily flickering light stimulation (1 hour/day) at individualized gamma frequency, and 12 completed long-term follow-up. Participants were classified post hoc as ICF+ (CF increase [≥]2 Hz; n=5) or ICF- (no CF increase; n=7). MMSE trajectories from baseline to week 12 and from week 12 to final follow-up were analyzed using piecewise linear mixed-effects models. ResultsBaseline characteristics, including MMSE, did not differ significantly between groups. During intervention, MMSE was stable in ICF+ (+0.27 points/month; 95% CI, -0.20 to 0.73) but declined in ICF- (-0.69 points/month; 95% CI, -1.07 to -0.30; between-group p=0.011). After cessation, estimated slopes were similar in ICF+ and ICF- (-0.16 vs -0.17 points/month; p=0.968), and the phasexgroup interaction was significant (p=0.006). Medication intensification during follow-up was more common in ICF-, including antipsychotic initiation in 4 of 7 participants. ConclusionsIn this exploratory post hoc analysis, lack of CF plasticity was associated with accelerated cognitive decline during the intervention phase but not during follow-up. This temporal pattern is consistent with, but does not establish, a dechallenge-like safety signal. Given the small sample, post hoc stratification, and differential medication changes, these findings should be considered hypothesis-generating and require prospective validation with pre-defined electrophysiologic stratification. Trial registrationClinical Research Information Service (CRIS), Republic of Korea (KCT0010618); submitted 6 October 2022; first patient enrolled 2 February 2023. https://cris.nih.go.kr/cris/search/detailSearch.do?seq=31321.