Post-traumatic dementia: Advances in understanding neurodegenerative mechanisms

Traumatic brain injury can trigger long-term neurodegenerative diseases beyond its devastating acute effects. This narrative review summarizes current understanding of the neurodegenerative mechanisms underlying post-traumatic dementia. Core mechanisms involve multiple pathophysiological processes: long-term dysfunction of the blood-brain barrier, which impairs the clearance of toxic proteins; diffuse axonal injury, leading topersistent disruption of axonal transport, dysregulation of calcium homeostasis, and Wallerian-like degeneration; and the abnormal deposition of key pathological proteins such as amyloid-β, hyperphosphorylation and propagation of tau protein, and dysfunctional TAR DNA-binding protein-43, all of which disrupt protein homeostasis. In addition, chronic neuroinflammation mediated by microglia and astrocytes acts as a critical link, continuously exacerbating synaptic damage and neurodegeneration through the release of pro-inflammatory factors. Genetic factors, such as the APOE4 allele, can significantly amplify these pathological processes. Collectively, this evidence indicates that traumatic brain injury is not an isolated acute event but rather initiates and accelerates a long-term, multifactorial neurodegenerative cascade, ultimately resulting in cognitive dysfunction. These insights provide important targets for the development of targeted intervention strategies.