{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:02:02Z","timestamp":1789984922143,"version":"4.0.1"},"reference-count":65,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease is a multifactorial neurodegenerative disorder in which amyloid-\u03b2 accumulation, tau pathology, neuroinflammation, synaptic dysfunction, vascular injury, and neuronal loss interact across multiple cellular compartments. Although amyloid and tau remain central to disease definition and biomarker staging, growing evidence indicates that inflammatory and regulated cell-death pathways actively shape disease progression. Receptor-interacting protein kinase 1 (RIPK1) has emerged as a context-dependent signaling checkpoint that links inflammatory signaling to cell-fate decisions. In its scaffold and ubiquitinated forms, RIPK1 supports TNFR1-associated NF-\u03baB and MAPK signaling, whereas RIPK1 kinase activation can promote apoptosis and RIPK1-RIPK3-MLKL-dependent necroptosis when regulatory checkpoints fail. In Alzheimer\u2019s disease, RIPK1 signaling has been implicated in disease-associated microglial responses, impaired amyloid-\u03b2 handling, astrocyte reactivity, tau-associated neuronal stress, neurovascular dysfunction, and necroptotic cell death. Here, we review the molecular regulation of RIPK1; evaluate evidence from human tissue, experimental models, and cellular systems; and discuss how RIPK1 may function as a convergence and amplification node linking amyloid-\u03b2, tau, neuroinflammation, and regulated cell death. We also examine the therapeutic rationale for targeting RIPK1, including CNS-penetrant inhibitors, biomarker challenges, timing of intervention, patient selection, and safety considerations. We propose that RIPK1 is an understudied pathway in Alzheimer\u2019s disease pathogenesis and that defining its cell-type-specific and stage-dependent functions will be essential to determine whether RIPK1 inhibition can be developed as a disease-modifying therapeutic strategy.<\/jats:p>","DOI":"10.3390\/cells15181692","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RIPK1 in Alzheimer\u2019s Disease: A Context-Dependent Signaling Hub Linking A\u03b2, Tau, Neuroinflammation, and Regulated Cell Death"],"prefix":"10.3390","volume":"15","author":[{"given":"Antonella","family":"Caccamo","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Lanza","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Casili","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7304-7430","authenticated-orcid":false,"given":"Salvatore","family":"Oddo","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1038\/s43587-024-00675-3","article-title":"A clinical perspective on the revised criteria for diagnosis and staging of Alzheimer\u2019s disease","volume":"4","author":"Hansson","year":"2024","journal-title":"Nat. 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