Objective: This study examined the relationships between renal function, measured by cystatin C, and brain small vessel disease (SVD), gray matter (GM) volume and cognition, in cognitively normal elderly subjects. Background Kidney dysfunction is related to neurological disorders, including cerebrovascular and cognitive syndromes. Cystatin C is a measure of kidney function that is considered to be more sensitive than creatinine in the elderly. Previous studies have linked higher cystatin C levels to subclinical brain infarcts and white matter lesions and to a higher incidence of cognitive impairment. Design/Methods: We analyzed demographic, medical, biochemical, neuropsychological, and brain imaging data from 735 cognitively normal subjects from the Cardiovascular Health Cognition Study. The GM volumes were analyzed using Voxel-Based Morphometry. Visual ratings of white matter lesions are used to determine the severity of brain SVD. Results: Elevated cystatin C levels were associated with lower neuropsychological test scores, greater prevalence of brain infarcts, higher white matter grade (WMG), and GM atrophy. Brain SVD was independently associated with higher serum cystatin C concentrations. In adjusted models, cystatin C levels also were significantly associated with GM volume only until body mass index (BMI) and WMG were added to the model. This finding suggests that the statistical effect of cystatin C on GM volume is mediated by these two variables. The VBM analysis found that higher cystatin C levels were associated with lower GM volume. Conclusions: Cystatin C levels are associated with structural brain changes, especially brain SVD and GM volume loss. These findings are consistent with the hypothesis that age-related vascular disease creates a vulnerability state for cognitive decline and dementia, possibly due to a decrease in brain reserve. Disclosure: Dr. Riverol has nothing to disclose. Dr. Becker has nothing to disclose. Dr. Lopez has received personal compensation for activities with Lundbeck and Johnson & Johnson as a consultant. Dr. Raji has nothing to disclose. Dr. Thompson has nothing to disclose. Dr. Carmichael has nothing to disclose. Dr. Gach has nothing to disclose. Dr. Longstreth has nothing to disclose. Dr. Fried has received personal compensation for activities with Pfizer Inc and Bayer Pharmaceuticals as a consultant. Dr. Fried has received personal compensation in an editorial capacity for ACP. Dr. Fried has received research support from Merck & Co., Inc. and Roche Diagnostics. Dr. Tracy has nothing to disclose. Dr. Kuller has nothing to disclose.