Neurobiological mechanisms of 40-Hz stimulation in Alzheimer's disease: evidence, heterogeneity, and constraints.

Early disruption of gamma oscillations is increasingly recognized as a contributor to neurodegeneration and cognitive decline in Alzheimer's disease (AD), positioning 40-Hz stimulation as a promising neuromodulatory strategy. However, its neurophysiological and cognitive effects remain highly variable across studies, underscoring the need for a more integrated mechanistic framework. This review synthesizes current evidence on the neurobiological mechanisms engaged by 40-Hz stimulation in AD, including circuit-, cellular-, and system-level processes underlying network dynamics, glial responses, and multi-target biological effects. We further highlight the conceptual distinction between "physiological resonance" and "artificial superimposition" as a potential determinant of deep-brain engagement and therapeutic outcomes. By integrating both supportive and conflicting findings, we highlight disease stage, biological sex, and behavioral state as important contributors to the heterogeneity of 40-Hz stimulation outcomes. Building on these observations, we propose that future research should move toward mechanistic stratification and precision neuromodulation to facilitate clinical translation.