From Traumatic Brain Injury to Alzheimer’s Disease: Multilevel Biomechanical, Neurovascular and Molecular Mechanisms with Emerging Therapeutic Directions

Traumatic brain injury (TBI) is increasingly recognized as a major risk factor for chronic neurodegenerative disease, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD). Biomechanical forces during head trauma, particularly rota-tional acceleration and angular deformation, produce diffuse axonal injury (DAI) and widespread white matter damage that trigger persistent neurobiological cascades. These include axonal transport failure, blood-brain barrier (BBB) disruption, neuroinflamma-tion, neurovascular and mitochondrial dysfunction, and pathological protein aggrega-tion, closely paralleling core features of AD. Epidemiological data support a dose-response relationship between TBI severity or repetition and subsequent dementia risk, moderated by genetic factors such as apolipoprotein E4 (ApoE4). Converging ex-perimental and early clinical studies have begun to target shared injury and neuro-degenerative pathways through acute neuroprotection, stem cell-based strategies for BBB restoration and neural repair, transcriptional and hormonal modulation, mitochondrial stabilization, and immunomodulation of chronic inflammation. This review systemati-cally synthesizes evidence linking biomechanical injury to molecular and neurovascular pathways of neurodegeneration, and summarizes emerging temporally targeted inter-ventions. By integrating mechanistic and therapeutic perspectives, we aim to narrow the translational gap between TBI and AD, refine identification of at-risk populations, and inform priorities for prevention and development of disease-modifying therapies.