Neuroinflammation and Its Role in Alzheimer’s Disease from Molecular Mechanisms to Therapeutic Targets

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic failure, and extensive neuronal loss. Growing evidence identifies neuroinflammation as a central and active participant in the pathophysiology of AD rather than a secondary response to amyloid-β (Aβ) accumulation or tau hyperphosphorylation. Persistent activation of microglia, astrocytes, and peripheral immune cells promotes a pro-inflammatory milieu that accelerates Aβ deposition, enhances tau pathology, disrupts neuronal signaling, and compromises neurovascular function. This review critically examines the molecular and cellular mechanisms by which neuroinflammation contributes to AD progression, emphasizing the roles of microglial receptors such as toll-like receptors (TLRs), TREM2, and components of the NLRP3 inflammasome in regulating phagocytosis, cytokine release, and glial metabolic states. Astrocytic reactivity, particularly the shift toward neurotoxic A1 phenotypes, is explored in relation to impaired glutamate homeostasis, synaptic degradation, and blood–brain barrier dysfunction.

Further attention is given to the complex crosstalk between central and peripheral immune systems, including the influence of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, chemokine-driven immune recruitment, complement system activation, and chronic systemic inflammation. Genetic and molecular determinants including APOE ε4, TREM2 mutations, and other immune-related risk alleles are evaluated for their impact on lipid metabolism, microglial responsiveness, Aβ clearance efficiency, and susceptibility to neurodegeneration. Additionally, emerging research on microbiome-immunity interactions, oxidative stress pathways, and metabolic dysregulation provides new insight into the interconnected nature of inflammatory and neurodegenerative processes in AD.

This review also assesses current and emerging therapeutic strategies that target neuroinflammation. These include inhibitors of inflammasome activation, cytokine-neutralizing antibodies, complement inhibitors, microglial phenotype modulators, and pharmacological agents that enhance adaptive immune regulation or promote Aβ clearance. Innovative approaches such as nanoparticle-based drug delivery, gene-editing technologies, and lifestyle-driven anti-inflammatory interventions are considered for their potential to improve treatment specificity, reduce off-target effects, and modify disease trajectory. Despite advances in understanding immune mechanisms in AD, challenges remain regarding the timing, safety, and individualized application of immunomodulatory therapies.

Overall, delineating the multifaceted role of neuroinflammation in AD offers essential insights for developing more effective disease-modifying treatments. Integrating mechanistic understanding with translational therapeutic strategies may enable more precise modulation of immune pathways to slow or prevent neurodegeneration and improve clinical outcomes in Alzheimer’s disease.