Advanced brain imaging revealed that amyloid-β plaques trigger harmful astrocyte activation only when microglia are simultaneously activated across cortical regions. The study tracked 101 individuals using three specialized PET tracers alongside plasma biomarkers, demonstrating that microglia act as essential intermediaries in the amyloid-astrocyte cascade leading to tau pathology and cognitive decline. This cellular triangle—amyloid deposits, activated microglia, and reactive astrocytes—represents a critical mechanistic pathway where immune dysfunction amplifies protein aggregation damage. The finding challenges models that position amyloid as directly neurotoxic, instead suggesting microglia serve as molecular switches that either contain or propagate amyloid's harmful effects. For therapeutic development, this implies that simply reducing amyloid may prove insufficient without addressing microglial dysfunction. The research builds on emerging evidence that neuroinflammation precedes rather than follows neurodegeneration, potentially explaining why anti-amyloid therapies have shown limited clinical benefit. The microglia-gating mechanism could explain individual variations in Alzheimer's progression and suggests that anti-inflammatory approaches targeting microglial activation might prove more effective than amyloid-clearing strategies alone, particularly in early-stage intervention.