Abstract Introduction Exposure to traumatic brain injury is a core risk factor that predisposes an individual to sporadic neurodegenerative diseases. We provide evidence that mechanical stress increases brain levels of hallmark proteins associated with neurodegeneration. Methods Wild‐type mice were exposed to multiple regimens of repetitive mild traumatic brain injury, generating a range of combinations of impact energies, frequencies, and durations of exposure. Brain concentrations of amyloid β 1–42 (Aβ 1–42 ), total tau, and α‐synuclein were measured by sandwich enzyme‐linked immunosorbent assay. Results There was a highly significant main effect of impact energy, frequency, and duration of exposure on Aβ 1–42 , tau, and α‐synuclein levels ( P < .001), and a significant interaction between impact energy and duration of exposure for Aβ 1–42 and tau ( P < .001), but not for α‐synuclein. Discussion Dose‐dependent and cumulative influence of repetitive mild traumatic brain injury–induced mechanical stress may trigger and/or accelerate neurodegeneration by pushing protein concentration over the disease threshold.