Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuronal loss. Although amyloid-β plaques and neurofibrillary tangles have been the historical hallmarks of AD pathology, growing evidence highlights microglial-mediated neuroinflammation as a central driver of disease onset and progression. This review aims to provide an updated overview of the dual roles of microglia in AD, from their protective functions to their contribution to chronic inflammation and neurodegeneration. Methods: This review synthesizes findings from recent experimental and clinical studies to examine the molecular mechanisms underlying microglial activation and dysfunction in AD. Key areas of focus include microglial signaling pathways, gut–brain axis interactions, and immunometabolic regulation. The review also evaluates emerging immunomodulatory therapeutic strategies designed to restore microglial homeostasis. Results: Recent studies reveal that microglia undergo a dynamic transition from a homeostatic to a reactive state in AD, contributing to sustained neuroinflammation and impaired clearance of pathological aggregates. Molecular mechanisms such as TREM2 signaling, NLRP3 inflammasome activation, and metabolic reprogramming play critical roles in this process. Additionally, gut microbiota alterations and systemic inflammation have been shown to influence microglial function, further exacerbating disease pathology. Conclusions: Targeting microglial dysfunction through immunomodulatory strategies holds promise as a disease-modifying approach in AD. Therapeutic avenues under investigation include natural compounds, synthetic modulators, immunotherapies, and microbiota-based interventions. A deeper mechanistic understanding of microglial regulation may open new translational pathways for the development of effective treatments for AD.
Erdağ et al. (Wed,) studied this question.