Identifying genetic variants for amyloid β in subcortical vascular cognitive impairment

BackgroundThe genetic basis of amyloid beta (A beta) deposition in subcortical vascular cognitive impairment (SVCI) is still unknown. Here, we investigated genetic variants involved in A beta deposition in patients with SVCI. MethodsWe recruited a total of 110 patients with SVCI and 424 patients with Alzheimer's disease-related cognitive impairment (ADCI), who underwent A beta positron emission tomography and genetic testing. Using candidate AD-associated single nucleotide polymorphisms (SNPs) that were previously identified, we investigated A beta-associated SNPs that were shared or distinct between patients with SVCI and those with ADCI. Replication analyses were performed using the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Rush Memory and Aging Project cohorts (ROS/MAP). ResultsWe identified a novel SNP, rs4732728, which showed distinct associations with A beta positivity in patients with SVCI (P-interaction = 1.49 x 10(-5)); rs4732728 was associated with increased A beta positivity in SVCI but decreased A beta positivity in ADCI. This pattern was also observed in ADNI and ROS/MAP cohorts. Prediction performance for A beta positivity in patients with SVCI increased (area under the receiver operating characteristic curve = 0.780; 95% confidence interval = 0.757-0.803) when rs4732728 was included. Cis-expression quantitative trait loci analysis demonstrated that rs4732728 was associated with EPHX2 expression in the brain (normalized effect size = -0.182, P = 0.005). ConclusionThe novel genetic variants associated with EPHX2 showed a distinct effect on A beta deposition between SVCI and ADCI. This finding may provide a potential pre-screening marker for A beta positivity and a candidate therapeutic target for SVCI.