Optical Conductivity as a Stage-Sensitive Imaging Biomarker for Alzheimer's Disease

Early detection of Alzheimer's disease (AD) remains limited by the inability of current imaging biomarkers to capture dynamic tissue changes preceding overt neurodegeneration. Conventional approaches primarily reflect molecular burden or structural atrophy and incompletely characterize the intermediate microenvironmental remodeling linking early pathology to clinical progression. Here, we introduce optical conductivity as a novel imaging biomarker characterizing tissue responses to optical-frequency electromagnetic fields. Using an optical wave tomography (OWT) framework, optical conductivity is reconstructed from diffuse optical measurements by integrating absorption-driven energy deposition with microstructure-dependent field redistribution. Applied to an APP/PS1 mouse model across young and old cohorts, optical conductivity revealed a significant age-by-disease interaction (F = 9.20, p = 0.0071). Quantitatively, its value was reduced in young AD animals relative to controls (~13%; Cohen's d = 1.93) but showed attenuation or reversal in older animals, indicating a stage-dependent crossover. Consistently, optical conductivity achieved strong classification performance in the young cohort (AUC = 0.80), outperforming absorption and exceeding scattering, with improved performance via multimodal integration (AUC = 0.87). Together, these findings suggest that optical conductivity captures stage-dependent microenvironmental remodeling not detectable by conventional optical parameters, offering potential for early detection and disease staging.