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

Abstract

Abstract 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.