Feasibility of immersive 40 Hz gamma sensory stimulation in early-stage Alzheimer's disease

Alzheimer's disease (AD) remains in need of effective therapeutic strategies that are safe, scalable, and broadly accessible. Gamma sensory stimulation (GSS) is a non-invasive neuromodulation approach under investigation as a potential intervention for AD, supported by a favorable safety profile and emerging evidence of biological and clinical effects. This study evaluates the feasibility of delivering immersive GSS through virtual reality (VR) in individuals with early-stage AD. In this single-session, within-subject, sham-controlled early feasibility study, 11 participants with mild cognitive impairment due to AD or mild AD underwent immersive audiovisual stimulation delivered via VR while electroencephalography (EEG) was recorded. Participants engaged in three VR environments of increasing visual and cognitive complexity, in which audiovisual content was modulated at 40 Hz; two environments also included a sham condition. Primary outcomes were safety, tolerability, and 40 Hz neural responses. Secondary analyses compared neural responses and recall and recognition of encoded video-word pairs between 40 Hz and sham stimulation. All participants completed the session without serious adverse events or discontinuations. Stimulation-emergent symptoms were predominantly absent or mild. 40 Hz GSS elicited significantly stronger EEG responses at the stimulation frequency than both baseline and sham stimulation (p < 0.001), confirming target engagement. In exploratory analyses, items encoded during 40 Hz stimulation were better recalled and recognized than those encoded during sham stimulation (all FDR-adjusted p < 0.05). In this single-session study, immersive GSS was well tolerated and elicited frequency-specific 40 Hz EEG responses in individuals with early-stage AD, with no serious safety concerns identified, supporting the feasibility of this delivery approach. The encouraging acute neural and task-specific behavioral differences between 40 Hz and sham stimulation are hypothesis-generating and motivate controlled pilot studies evaluating the effects of repeated use on validated cognitive and functional outcomes.