TNF inhibition differentially impacts regional Abeta immunotherapy efficacy in the humanized hAb

backgroundThe FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer's disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development.

methodsThis study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes.

resultsIn this study, we established ARIA-H pathology in a humanized mouse model (hAβ

conclusionWe induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.