Targeting Microglial Receptors for Alzheimer’s Disease: Translational Barriers from Bench to Bedside

Abstract

Alzheimer’s disease (AD) remains a major neurodegenerative challenge with limited therapeutic options. Microglia, the resident immune cells of the central nervous system, shape key pathological processes in AD, including amyloid-beta (Aβ) clearance, neuroinflammation, tau pathology, and synaptic homeostasis. Accordingly, microglial receptors that regulate microglial sensing, phagocytosis, and inflammatory signaling have emerged as candidates for disease-modifying interventions. However, translation from preclinical discovery to clinical benefit is impeded by multiple barriers, including stage-dependent receptor functions, peripheral off-target effects, compensatory signaling within interconnected receptor networks, biomarker deficiencies, and species differences, all of which are key bottlenecks detailed in this review. We summarize preclinical and clinical progress in therapeutics targeting microglial receptors; analyze these critical translational bottlenecks; and discuss potential strategies including precision delivery, humanized experimental systems, and biomarker-forward trial designs, with the goal of supporting rigorously designed and biomarker-informed clinical translation.