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Continuous activation of TNF-\u03b1 leads to synaptic dysfunction, neuronal loss, and worsening of amyloid and tau pathology. Specifically, the upregulation of the pro-inflammatory cytokine TNF-\u03b1 in the brain activates its receptors (TNFR1 &amp; TNFR2). Targeting TNF-\u03b1 through selective inhibition presents a promising therapeutic strategy for regulating neuroinflammatory responses without compromising systemic immunity. This review discusses current insights into TNF-\u03b1 signaling in AD progression and examines the effectiveness of selective TNF-\u03b1 inhibitors in preclinical and clinical studies. We also highlighted specific TNF-\u03b1 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-\u03b1 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.<\/jats:p>","DOI":"10.1007\/s10753-026-02492-9","type":"journal-article","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T20:23:46Z","timestamp":1773519826000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Selective Inhibition of Tumor Necrosis Factor for Attenuating Alzheimer\u2019s Disease: Strategies Targeting Neuroinflammation"],"prefix":"10.1007","volume":"49","author":[{"given":"Janakiraman Pillai","family":"Udaiyappan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rengasamy","family":"Balakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manivasagam Muthukumaran","family":"Tamilarasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balamuralikrishnan","family":"Balasubramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasim Sakran","family":"Abass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,14]]},"reference":[{"key":"2492_CR1","unstructured":"Global action plan on the public health response to dementia 2017\u20132025. https:\/\/www.who.int\/publications\/i\/item\/global-action-plan-on-the-public-health-response-to-dementia-2017---2025."},{"key":"2492_CR2","doi-asserted-by":"publisher","unstructured":"2023. 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