Therapeutic potential of 40 Hz flickering light stimulation in Alzheimer's disease: Mechanisms,evidence,and controversies

Abstract

Gamma oscillations (30–100 Hz), generated by the synchronized firing of neurons, play a crucial role in memory storage and retrieval. Non-invasive 40 Hz flickering light stimulation (FLS) has been shown to induce gamma oscillations, leading to beneficial effects including microglial activation, increased vascularization, and enhanced glymphatic clearance. These effects correlate with reduced amyloid-β (Aβ) pathology in animal models of Alzheimer's disease (AD). However, recent studies in mouse models report contradictory findings, challenging the efficacy of 40 Hz FLS in generating widespread gamma entrainment and reducing Aβ load or microglial response. By examining the putative causal links between gamma oscillations and AD pathogenesis, critically comparing methodological differences and outcomes of key studies, and synthesizing current evidence, we evaluate the therapeutic potential of 40 Hz FLS for AD. While gamma induction may underlie FLS-mediated amelioration of AD pathology, methodological discrepancies and unresolved controversies underscore the need for further investigation to determine its therapeutic validity and clinical potential.