Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer’s Disease Model

Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer’s disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate microglial activation in response to chronic Aβ-mAb therapy and its modulation by the PPAR-γ agonist pioglitazone. AppNL-G-F knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that were attenuated by pioglitazone co-treatment. Both mono- and combination therapy modulated the temporal and spatial dynamics of the TSPO-PET signal. In addition, we derived a microglial desynchronization index from TSPO-PET connectivity, which captured individual neuroimmune responses and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help to differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. In summary, TSPO-PET enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD.