CSF sTREM2 is associated with distinct microglial responses with separate effects on Alzheimer's pathology in the disease's trajectory

TREM2 associations suggest distinct and diverging stage-dependent microglial responses in AD, with a neurotoxic Aβ-dependent response in Aβ-MCI. In Aβ+MCI, the microglial response is associated with preserved cognition, suggesting a neuroprotective phenotype has emerged in response to high amyloid load. In AD, the response turns neurotoxic again as pathology continues to accumulate. References 1. Heneka MT, et al. Neuroinflammation in Alzheimer disease. Nat Rev Immunol. Dec 9 2024;doi:10.1038/s41577-024-01104-7 2. Boche D, Nicoll JAR. Invited Review - Understanding cause and effect in Alzheimer's pathophysiology: Implications for clinical trials. Neuropathol Appl Neurobiol. Dec 2020;46(7):623-640.doi:10.1111/nan.12642 3. Valiukas Z, et al. Microglial activation states and their implications for Alzheimer's Disease. J Prev Alzheimers Dis. Jan 2025;12(1):100013.doi:10.1016/j.tjpad.2024.100013 4. Nguyen AT, et al. APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer's disease. Acta Neuropathol. Oct 2020;140(4):477-493.doi:10.1007/s00401-020-02200-3.