Target-area dosimetry-guided photobiomodulation improves pathology and cognitive function in APPswe/PS1dE9 mice

Photobiomodulation (PBM) has shown potential in Alzheimer's disease (AD) models, but substantial heterogeneity in irradiation parameters and the lack of intracerebral dose quantification have limited reproducibility and mechanistic interpretation. In transcranial PBM, surface power density does not reliably reflect energy delivery to brain targets due to wavelength-dependent tissue attenuation.

We developed a target-area dosimetry- guided PBM framework by integrating Monte Carlo-based light transport modeling with inverse calibration for selected representative wavelength-target conditions. Based on these simulations, inverse calibration was performed for selected representative wavelength-target combinations, with 810 nm irradiation optimized for PFC-directed PBM and 1060 nm, 40 Hz pulsed irradiation optimized for HIPP-directed PBM. APPswe/PS1dE9 mice received region-oriented and comparative PBM treatments, followed by behavioral, pathological, and electrophysiological assessments.

Monte Carlo simulations revealed marked wavelength-dependent differences in intracerebral light distribution under identical surface irradiation. Inverse calibration supported the selection of region-specific irradiation parameters and highlighted the need to consider target-area light exposure rather than surface power alone. Among the tested irradiation conditions, PBM improved spatial learning and memory and modulated amyloid burden, neuroinflammatory responses, synaptic markers, and neural network activity. Among these treatments, combined hippocampal irradiation with 810 nm and 1060 nm light produced the most consistent overall responses, while 810 nm PFC irradiation also showed beneficial effects across several outcome measures.

These findings support target-area dosimetry as an important physical consideration for the design and interpretation of region-oriented PBM protocols in AD models. By integrating intracerebral light propagation modeling with biological evaluation, this study provides a methodological framework for improving PBM parameter selection and guiding future optimization of transcranial PBM interventions.