Traumatic Brain Injury and the Road to Alzheimer's Disease.

Alzheimer's disease (AD) is associated with both mild and moderate to severe traumatic brain injury (TBI). This narrative review gives an account of the association of TBI and AD and highlights possible cellular and molecular pathways linking these pathologies. Following TBI, the immune system of the brain is rapidly activated and gives rise to acute neuroinflammation. While neuroinflammation is protective in nature, it may persist chronically in the case of less-controlled prolonged responses, triggering neuroprotective loss and neurotoxicity. Moreover, reduced clearance of amyloid-beta may occur, along with its overproduction and aggregation. Tau protein regulation is also altered by kinase and phosphatase enzymes, resulting in the accumulation of hyperphosphorylated tau protein in neurons and glial cells and the emergence of intracellular tau neurofibrillary tangles. More to the point, vascular impairment following TBI has been reported to contribute to cognitive decline and AD. Blood-brain barrier breakdown following TBI allows for infiltration of peripheral immune cells and blood-derived proteins into the brain, which exacerbates neuroinflammation, interrupts synaptic signaling, and promotes oxidative stress. The neuroinflammatory response, dynamic alterations in amyloid and tau biology, and vascular impairment are thought to interact within a broader network of processes associated with AD neurodegeneration, rather than acting as isolated mechanisms.