Selective Inhibition of Tumor Necrosis Factor for Attenuating Alzheimer's Disease: Strategies Targeting Neuroinflammation.

Neuroinflammation is increasingly recognized as a key feature in the development of Alzheimer’s disease (AD), with tumor necrosis factor-alpha (TNF-α) playing a crucial role in initiating inflammatory responses. Continuous activation of TNF-α leads to synaptic dysfunction, neuronal loss, and worsening of amyloid and tau pathology. Specifically, the upregulation of the pro-inflammatory cytokine TNF-α in the brain activates its receptors (TNFR1 & TNFR2). Targeting TNF-α through selective inhibition presents a promising therapeutic strategy for regulating neuroinflammatory responses without compromising systemic immunity. This review discusses current insights into TNF-α signaling in AD progression and examines the effectiveness of selective TNF-α inhibitors in preclinical and clinical studies. We also highlighted specific TNF-α inhibitors, including small molecules and gene therapy approaches, for chronic inflammatory conditions and discussed the limitations and future directions of the current review. Targeted TNF-α inhibition could serve as a novel, disease-modifying treatment for AD, especially when combined with multi-targeted approaches addressing amyloid burden, tau pathology, oxidative stress, and neuroinflammation.