Depletion of microglial compensation in glial network: Disease‐associated response dynamics in the revised amyloid hypothesis

Abstract Microglia mount coordinated, stage‐dependent compensatory programs in response to early amyloid β (Aβ) accumulation that preserve proteostasis and neuronal integrity during preclinical Alzheimer's disease. We propose the “microglial compensation‐depletion” framework that describes a distributed compensatory network whose failure constitutes a mechanistic tipping point. Once compensatory capacity falls below a critical threshold, positive‐feedback loops amplify irreversible pathology, eventually leading to cognitive decline. Integrating single‐cell transcriptomics, chromatin accessibility, and genetic evidence from human cohorts and animal models, we synthesize evidence for stage‐dependent microglial transitions and for glial interactions that shape resilience or vulnerability. The microglial compensation‐depletion framework in the revised amyloid hypothesis is a multiscale, dynamical perspective and highlights potential strategies for modeling and clinical intervention. Intercellular ligand–receptor networks may provide quantitative substrates for defining glial‐state patterns and even identifying key communication axes that delineate transitions. For example, microglial triggering receptor expressed on myeloid cells 2 (TREM2)–apolipoprotein E (APOE) signaling exemplifies an intercellular axis that modulates microglial phenotype and Aβ handling. Clinically, in vivo imaging and biofluid biomarkers may offer potential means to track glial functional reserve and to detect approaching tipping points.