Shotgun proteomics using liquid chromatography tandem mass spectrometry (LC MS/MS) can characterize in-depth human cerebrospinal fluid (CSF) and plasma proteomes. Nonetheless, association between the proteomes in each compartment has not been described to the full extent using such technology due to sample size limitations. We deployed MS-based proteomics in paired CSF and plasma samples volunteered by 120 elders with (n = 72) and without cognitive impairment (n = 48) to comprehensively examine the compartmental differences and the influence of blood-brain barrier (BBB) integrity. We further tested the hypothesis that BBB breakdown can be identified from CSF and plasma proteome alterations in non-demented elders.