Thermodynamic impedance mismatch in neurodegeneration: A biophysical framework for the prediction of amyloid-related imaging abnormalities.

Amyloid-related imaging abnormalities (ARIA) represent a significant iatrogenic complication of anti-amyloid monoclonal antibody therapies. To address this, we propose the Impedance Mismatch Theory as a theoretical framework and hypothesis, reframing neurodegeneration as a network-level thermodynamic failure characterized by localized thermal runaway (Neural Physiological Load Index (NLI) greater than or equal to 1.0). Within this framework, amyloid-β (Aβ) is modeled not only in its established biological context, but as a potential thermodynamic heat sink and bio-conductive electrical shunt deployed to protect hyper-metabolic neural hubs. Utilizing the Pennes bioheat equation, we formalize the NLI and map its theoretical values to absolute 1H-magnetic resonance spectroscopy thermometry signatures. Our model suggests that clearing Aβ in the setting of unresolved energetic mismatch could contribute to localized mechanical and thermal instability. We hypothesize that these upstream physical dynamics precipitate the downstream inflammatory cascades clinically observed as ARIA. If validated, these theoretical considerations suggest that effective disease modification may require thermodynamic normalization as a prerequisite to, or in parallel with, plaque clearance.