Frequency-Specific Transcranial Photobiomodulation Elicits Complementary Glial Mechanisms for Neurovascular Protection and Amyloid Clearance in Alzheimer Disease

Alzheimer disease (AD), a devastating neurodegenerative disorder, is pathologically defined by amyloid-β (Aβ) deposition and neurofibrillary tangles. Critically, concomitant cerebrovascular dysfunction compromises neuronal homeostasis and significantly accelerates AD progression by impairing the neurovascular unit. However, effective strategies to modulate this complex neurovascular pathology remain unclear. Here, we applied transcranial photobiomodulation (tPBM) with continuous-wave (CW) and 40-Hz pulsed light to target neurovascular pathology in 5xFAD mice. The results showed that both tPBM modalities comparably ameliorated cognitive dysfunction through distinct glial-mediated mechanisms. Specifically, CW light primarily enhanced astrocyte–vascular coupling, which ameliorated vascular dysfunction and protected synapses. In contrast, 40-Hz light predominantly drove spatial redistribution of microglia toward Aβ plaques, thereby enhancing localized amyloid clearance. These findings reveal complementary pathways for tPBM in AD intervention, highlighting that CW and 40-Hz light offer modality-specific therapeutic advantages: The former targets cerebrovascular dysfunction, while the latter addresses Aβ plaque deposition. Collectively, our study provides critical mechanistic insights for optimizing tPBM protocols, establishing a foundation for more precise and comprehensive AD interventions.