Loss of calcium homeostasis, a shared feature of Alzheimer's Disease (AD) and Traumatic Brain Injury (TBI), activates enzyme-dependent cascades that promote protein misfolding, degrade synaptic architecture, impair axonal transport, and lead to neuronal death. Epidemiological studies identify TBI as a major risk factor for AD, yet the mechanistic basis for this association remains incompletely understood. Evidence from human and experimental studies implicate calcium dysregulation as a central link, triggering interconnected kinase, phosphatase, and protease networks that drive AD hallmark pathology, including amyloid-β (Aβ) accumulation and tau hyperphosphorylation. The calcium-dependent protease calpain is a key node in this network, regulating downstream enzyme activity, and cleaving essential scaffolding and signaling proteins. Selective vulnerability of the hippocampus and white matter to calcium-mediated damage may underlie cognitive deficits common to both conditions. In preclinical TBI and AD models, pharmacological inhibition of calcium-dependent enzymes confers neuroprotection. Recognizing disrupted calcium signaling as an upstream driver of post-traumatic neurodegeneration may enable early interventions to reduce AD risk among TBI survivors.
Neuschmid et al. (2025) studied this question.