Ionizing radiation and Alzheimer's disease: epidemiology, mechanisms, and eCIRP-mediated tau pathology.

As human radiation exposure expands through medical imaging, nuclear industry growth, and the acceleration of crewed space exploration, understanding the molecular mechanisms linking radiation to Alzheimer's disease (AD) is becoming an increasingly urgent priority. Here, we review epidemiological, mechanistic, and therapeutic evidence for a relationship between ionizing radiation and AD, focusing on a neuroinflammatory pathway centered on extracellular cold-inducible RNA-binding protein (eCIRP). Epidemiological support comes from occupational cohorts of nuclear workers and studies linking residential radon to AD mortality; a meta-analysis of 18 studies finds an 11% increased all-cause dementia risk per 100 mSv. Mechanistically, ionizing radiation generates DNA double-strand breaks and reactive oxygen species that activate the ataxia-telangiectasia mutated (ATM) kinase and trigger rapid microglial activation, and causes the nuclear-to-cytoplasmic translocation and extracellular release of the danger-associated molecular pattern eCIRP. Released eCIRP activates neuronal cyclin-dependent kinase 5 (Cdk5), resulting in AD-like tau phosphorylation. This pathway is validated by loss-of-function studies in CIRP-knockout mice and pharmacological blockade with the eCIRP inhibitor C23. Beyond tau phosphorylation, eCIRP drives mitochondrial dysfunction and ferroptosis in myeloid cells and activates endothelial cell death pathways that may compromise blood-brain barrier integrity. eCIRP links radiation-induced neuroinflammation to tau-driven neurodegeneration, and eCIRP inhibitors warrant investigation for both radiation-induced cognitive dysfunction and sporadic AD, where eCIRP is similarly elevated. Translating these mechanistic insights into eCIRP-targeted therapies and validated biomarkers could open a new front in the prevention and treatment of these prevalent and debilitating disorders.