RIPK1 in Alzheimer’s Disease: A Context-Dependent Signaling Hub Linking Aβ, Tau, Neuroinflammation, and Regulated Cell Death

Alzheimer’s disease is a multifactorial neurodegenerative disorder in which amyloid-β 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-κB and MAPK signaling, whereas RIPK1 kinase activation can promote apoptosis and RIPK1-RIPK3-MLKL-dependent necroptosis when regulatory checkpoints fail. In Alzheimer’s disease, RIPK1 signaling has been implicated in disease-associated microglial responses, impaired amyloid-β 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-β, 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’s 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.