Frailty is known to predict dementia. However, its link with neurodegenerative alterations of the central nervous system (CNS) is not well understood at present. We investigated the association between the biomechanical response of the CNS and frailty in older adults suspected of normal pressure hydrocephalus (NPH) presenting markers of multiple comorbid neurodegenerative pathologies. The biomechanical response of the CNS was characterized by the CNS elastance coefficient inferred from phase contrast magnetic resonance imaging and intracranial pressure monitoring during a lumbar infusion test. Frailty was assessed with an index of health deficit accumulation. We found a significant association between the CNS elastance coefficient and frailty, with an effect size comparable to that between frailty and age, the latter being the strongest known risk factor of frailty. Results were independent of CSF dynamics, showing they are not specific to the NPH neuropathological condition. The CNS biomechanical characterization may help to understand how frailty is related to neurodegeneration and detect the shift from normal to pathological brain ageing.