Molecular Mechanisms and Advances of Photobiomodulation for Alzheimer's Disease

Alzheimer’s disease (AD) is a complex neurodegenerative disorder. Current pharmacological interventions face challenges, including limited blood-brain barrier penetration and adverse effects. Red/near-infrared photobiomodulation (PBM) emerges as a promising non-invasive strategy targeting multiple AD pathologies simultaneously. Key molecular mechanisms include PBM-mediated activation of mitochondrial cytochrome c oxidase, enhancing ATP synthesis and reducing oxidative stress. Crucially, specific wavelengths such as 630 nm directly disassemble formaldehyde-crosslinked Aβ fibrils and restore formaldehyde dehydrogenase activity, breaking a pathogenic Aβ-formaldehyde cycle. PBM further reprograms microglial metabolism toward an anti-inflammatory phenotype, enhancing Aβ phagocytosis and suppressing pro-inflammatory cytokines. It also improves cerebrovascular function, augments glymphatic/meningeal lymphatic Aβ clearance, and restores synaptic plasticity and neural oscillations, correlating with cognitive improvements. Pilot clinical studies demonstrate enhanced cognitive function and functional connectivity following transcranial/intranasal PBM, with favorable safety. However, significant heterogeneity in treatment protocols (wavelength, fluence, pulsing) and questions regarding long-term efficacy necessitate rigorous standardization. Emerging combinatorial strategies integrating PBM with light-triggered nanomedicines offer enhanced BBB penetration and targeted Aβ disaggregation. Future directions emphasize interdisciplinary collaboration, biomarker-driven personalized dosing, and large-scale randomized controlled trials to realize PBM’s therapeutic potential for early AD intervention.