APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume

To assess apolipoprotein L1 gene (APOL1) renal-risk-variant effects on the brain, magnetic resonance imaging (MRI)-based cerebral volumes and cognitive function were assessed in 517 African American–Diabetes Heart Study (AA-DHS) Memory IN Diabetes (MIND) and 2568 hypertensive African American Systolic Blood Pressure Intervention Trial (SPRINT) participants without diabetes. Within these cohorts, 483 and 197 had cerebral MRI, respectively. AA-DHS participants were characterized as follows: 60.9% female, mean age of 58.6 years, diabetes duration 13.1 years, estimated glomerular filtration rate of 88.2 ml/min/1.73 m², and a median spot urine albumin to creatinine ratio of 10.0 mg/g. In additive genetic models adjusting for age, sex, ancestry, scanner, intracranial volume, body mass index, hemoglobin A1c, statins, nephropathy, smoking, hypertension, and cardiovascular disease, APOL1 renal-risk-variants were positively associated with gray matter volume (β = 3.4 × 10^–3) and negatively associated with white matter lesion volume (β = –0.303) (an indicator of cerebral small vessel disease) and cerebrospinal fluid volume (β= –30707) (all significant), but not with white matter volume or cognitive function. Significant associations corresponding to adjusted effect sizes (β/SE) were observed with gray matter volume (0.16) and white matter lesion volume (–0.208), but not with cerebrospinal fluid volume (–0.251). Meta-analysis results with SPRINT Memory and Cognition in Decreased Hypertension (MIND) participants who had cerebral MRI were confirmatory. Thus, APOL1 renal-risk-variants are associated with larger gray matter volume and lower white matter lesion volume suggesting lower intracranial small vessel disease.