Previously, we reported a defect in the blood-brain barrier (BBB) of apolipoprotein E-deficient (apoE-/-) mice (24). Here, we investigate BBB permeability in wild-type (WT) and apoE-/- mice as a function of age. Both WT and apoE-/- mice showed significantly increased cortical BBB leakage with age. However, in apoE-/- mice, the leakage increased at a 3.7 x higher rate compared with WT mice. Surprisingly, the cerebellum showed significantly more leakage than other brain regions across age, while there was no difference between the two hemispheres. To determine the contribution of tissue- vs. blood-borne apoE to vascular permeability, we generated chimeric mice by bone marrow transplantation and measured their BBB leakage. These experiments suggest that both blood- and tissue-derived apoE are equally important for BBB function. In sum, we find an age-dependent defect in the BBB that is exacerbated in apoE-/- mice. Since vascular defects are found in patients with age-related neurodegenerative diseases, such as Alzheimer's, age-related BBB leakage could underlie these defects and may thus be an important contributor to the cumulative neuronal damage of these diseases.