Reshaping the immune landscape: next-generation microglia-targeted therapies for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a significant global health challenge characterized as a multifactorial neurodegenerative disorder, involving amyloid-β (Aβ) and Tau aggregation, neuroinflammation and progressive neuronal injury. While Amyloid-targeted therapies have achieved a breakthrough in prevention of Aβ aggregation, the strategies face notable limitations in achieving curative outcomes and management of amyloid-independent central nervous system (CNS) dysfunction. Consequently, targeting microglia, the central immune cells of the brain, has emerged as a promising strategy to enhance the specificity and efficacy of AD interventions.

MAIN BODY: Accumulating evidence indicates microglial dysfunction is not a passive immune bystander of AD, but serves as a critical mechanistic nexus linking Aβ accumulation and AD symptomatic phenotype. This review critically examines the "next generation" of microglial therapeutics, moving beyond broad immunosuppression to precision phenotype modulation. We highlight breakthrough strategies in recent years including immune reconstitution, metabolic reprogramming, nanomaterial-mediated drug delivery, and the revolutionary potential of iPSC-derived microglia replacement. By elucidating the rationale underlying the specific strategies based on microglial biofunction and potential molecular mechanism in AD pathology, we provide an overview of current development of clinical trials and cutting-edge modalities aimed at restoring microglial homeostasis, affording an opportunity to alter the AD trajectory.

CONCLUSION: This review aims to delineate the path from bench to bedside and propose promising pathways to overcome current bottlenecks in AD drug development.