Conclusion

Current evidence indicates that the apparently opposing roles of NF-κB in AD reflect context-dependent regulation rather than a true biological paradox. Transient and appropriately controlled NF-κB signaling can support neuronal survival, stress adaptation, antioxidant defense, and selected compensatory responses, whereas persistent or disease-conditioned signaling—particularly RelA/p65-dominant activity—is more consistently associated with amyloidogenic processing, chronic neuroinflammation, tau-related pathology, impaired proteostasis, neurovascular dysfunction, and neuronal injury. These effects differ substantially according to cell type, upstream stimulus, signaling duration, dimer composition, and disease state.

Human genetic, postmortem, peripheral, and iPSC-based studies broadly have reinforced this framework, although each provided only a partial view of pathway regulation in the human brain. Importantly, impaired inducible NF-κB responsiveness may increase susceptibility to LOAD, while exaggerated or persistent signaling appears more prominent after pathological processes are established. Whether these states represent sequential phases of disease or distinct parallel forms of dysregulation remains unresolved.

Taken together, the evidence argues against global activation or inhibition of NF-κB as a therapeutic strategy. Future approaches should instead identify and selectively target disease-driving NF-κB programs within specific cellular and molecular contexts while preserving physiological signaling required for homeostasis and adaptive stress responses. Resolving the temporal, cell-specific, and molecular architecture of NF-κB signaling across the AD continuum will be essential for translating this pathway from a broadly implicated inflammatory regulator into a more precise therapeutic target.