Alzheimer's disease (AD) is increasingly recognized as a disorder driven by dysregulated innate immunity rather than merely amyloid‑β accumulation. Microglia, the brain's resident innate immune cells, acquire long‑term functional memory, a process known as trained immunity or innate immune memory, through epigenetic and metabolic reprogramming. In AD, chronic exposure to amyloid‑β and tau aggregates locks microglia into a maladaptive primed state characterized by altered histone modifications (H3K4me3, H3K27ac), sustained glycolysis via the HIF‑1α/mTOR axis, and impaired phagocytic function, perpetuating neuroinflammation and neurodegeneration. This review critically synthesizes recent advances that define the molecular architecture of microglial immune memory, including epigenetic rewiring, immunometabolic shifts, and intercellular crosstalk with astrocytes and the gut microbiome. We evaluate the emerging immunopharmacological toolbox designed to reverse maladaptive priming and restore neuroprotective resilience, focusing on small‑molecule NLRP3 inflammasome inhibitors (HT‑6184, DFV890, BGE‑102), TREM2 agonists (VG‑3927, MNA‑001), metabolic modulators (metformin, rapamycin), trained immunity‑based vaccination (BCG), specialized pro‑resolving mediators (maresin 1, resolvin D1, lipoxin A4), and senolytics. Clinical‑stage agents and their mechanisms of action are highlighted. We argue that the next generation of AD therapeutics must move beyond target suppression toward the functional reprogramming of brain innate immunity, and we propose a biomarker-guided, patient-stratified framework that integrates multimodal immunopharmacology, combining NLRP3 inhibition, TREM2 agonism, metabolic reprogramming, and resolution pharmacology to restore immune homeostasis. Harnessing the plasticity of innate immune memory offers a transformative paradigm for disease‑modifying therapy in AD.
