Exploring Neuroinflammatory Pathways in the Progression of Alzheimer's Disease

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease in the globe that impacts more than 55 million people and is estimated to exceed 150 million by 2050.Although amyloid-beta (Abb) plaques and neurofibrillary tangles (NFTs) built up of hyperphosphorylated tau protein are the neuropathological hallmarks of AD, increasing evidence is highlighting neuroinflammation as a primary and early-initiating process in the pathogenesis of the disease as opposed to secondary.Objectives: This review systematically reviews the molecular and cellular processes through which neuroinflammation contributes to AD progression, and questions the roles of microglia, astrocytes, the complement system, and peripheral immune infiltration.We also assess genetic risk architectures connecting immune dysfunction to AD susceptibility and assess new therapeutic approaches to neuroinflammatory pathways.Key Findings: Microglia transition from homeostatic to disease-associated states (DAM) in response to Aβ, with TREM2-dependent signaling being critical for plaque containment.Reactive astrogliosis inhibits neurotrophic support and worsens cytokine-mediated synaptic dysfunction.Immune pathways TREM2, APOE, CD33, and CR1 genetic variants are all implicated in AD pathogenesis.New therapeutics -such as anti-TREM2 antibodies, p38 MAPK inhibitors, and GLP-1 receptor agonists -provide mechanistically-based therapies to decrease neuroinflammatory cascades.Conclusions: Neuroinflammation is a therapeutically modifiable axis in AD that is not limited to amyloidbased paradigms.Highly targeted immunomodulatory approaches, preferably used during pre-symptomatic or early-symptomatic periods, have significant potential in terms of disease modification.