Notably, blocking APOE4-TGF-β1 signaling restores MGnD-like phenotypes and enhances Aβ clearance in AD models, highlighting the dual role of TGF-β1 in microglial function—maintaining homeostasis under physiological conditions but potentially impeding MGnD activation and Aβ clearance in AD pathology—thereby underscoring its complex interplay with the TREM2-APOE axis. Here, TREM2 is linked to Alzheimer disease.