Microglial dysfunction in Alzheimer's disease: Mechanisms, emerging therapies, and future directions.

Alzheimer's disease (AD) is a severe neurodegenerative condition characterized by progressive cognitive decline and behavioral changes. These symptoms are primarily driven by the accumulation of amyloid-beta (Aβ) plaques, tau tangles, and persistent neuroinflammation. Microglia, the brain's resident immune cells, play a crucial role in the disease's progression. Initially, these cells protectively respond to Aβ deposits, working to clear plaques and support neuronal health. However, prolonged activation of microglia leads to a transition from a neuroprotective state to a pro-inflammatory one, ultimately contributing to neuronal damage and worsening disease progression. This review explores the molecular mechanisms responsible for microglial dysfunction in AD, with a particular emphasis on key inflammatory pathways, including NF-κB, MAPK, and TLR4 signaling. These pathways drive the release of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, which further amplify neuroinflammation, disrupt synaptic plasticity, and contribute to neuronal loss. Additionally, emerging therapeutic strategies aimed at modulating microglial activity to reduce neuroinflammation and enhance Aβ clearance are examined. A key focus is placed on the future of AD research, emphasizing the importance of longitudinal studies to gain a deeper understanding of how microglia contribute to disease progression over time. The review also highlights the potential of personalized medicine, which seeks to tailor treatments based on an individual's unique genetic and environmental risk factors. Notably, genetic predispositions such as the APOE4 allele, along with environmental influences like air pollution and chronic infections, are identified as significant modulators of microglial activity. Given the complexity of AD, a comprehensive, multi-faceted approach will be essential for advancing research and developing more effective therapeutic interventions.