Review highlights microglia-targeted therapies as emerging Alzheimer's strategy beyond amyloid

While the recent approval of amyloid-beta (Aβ)-clearing monoclonal antibodies (mAbs) marks a milestone in treating Alzheimer’s disease (AD), their modest clinical efficacy has catalyzed a paradigm shift, underscoring the necessity of targeting complementary pathological drivers. Neuroinflammation, once considered a secondary phenomenon, is now established as a third core pathological pillar of AD, with microglia at its epicenter. This review provides a comprehensive analysis of the multifaceted role of microglia in AD pathogenesis and evaluates the rapidly evolving landscape of microglia-targeted therapeutic strategies. We first delineate the dynamic and dichotomous function of microglia, which act as a “double-edged sword.” Emerging evidence reveals a complex, three-stage functional arc: microglia are implicated in the initial seeding of Aβ plaques, then transition to a neuroprotective role by containing established plaques, and finally devolve into a chronic, pro-inflammatory state that drives neurodegeneration. We then delve into the core molecular mechanisms governing this plasticity, including the pivotal Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)-APOE signaling axis, the inhibitory receptor Cluster of Differentiation 33 (CD33), and key intracellular hubs like the NLRP3 inflammasome, which directly link genetic risk factors to microglial dysregulation. Based on this mechanistic understanding, we critically evaluate diverse therapeutic strategies, ranging from suppressing neurotoxic inflammation (e.g., TNF-α and NLRP3 inhibitors) to enhancing protective functions (e.g., TREM2 agonism and CD33 antagonism), eliminating senescent microglia (senolytics), and utilizing advanced nanoplatforms for brain-targeted delivery. Finally, we highlight the critical role of neuroinflammatory biomarkers within the emerging ATI(N) framework for enabling precision medicine. In conclusion, targeting microglia represents a vital therapeutic avenue that moves beyond amyloid-centric approaches, where a sophisticated understanding of their stage-dependent functions is paramount for developing effective immunomodulatory therapies to alter the devastating course of AD.