Loss of apolipoprotein E receptor LR11 in Alzheimer disease

Background: Genetic, epidemiologic, and biochemical evidence suggests that apolipoprotein E, low-density lipoprotein receptors, and lipid metabolism play important roles in sporadic Alzheimer disease (AD). Objective: To identify novel candidate genes associated with sporadic AD. Design: We performed an unbiased microarray screen for genes differentially expressed in lymphoblasts of patients with sporadic AD and prioritized I gene product for further characterization in AD brain. Setting: Emory University, Atlanta, Ga. Subjects: Cell lines were used from 14 patients with AD and 9 normal human control subjects. Results: Six genes were differentially expressed in lymphoblasts of 2 independent groups of patients with probable AD and autopsy-proven AD. We hypothesized that 1 of the genes, termed low-density lipoprotein receptor relative with I I binding repeats (LR11) (reduced 1.8- and 2.5-fold in AD lymphoblasts vs controls), might be associated with sporadic AD on the basis of its function as neuronal apolipoprotein E receptor. We found dramatic and consistent loss of immunocytochemical staining for LR1 I in histologically normal-appearing neurons in AD brains. This reduction of LR1 I protein was confirmed by quantitative Western blotting (P=.01). Conclusions: There is loss of the microarray-derived candidate, LR11, in neurons of AD brains. This study shows that microarray analysis of widely available lymphoblasts derived from patients with AD holds promise as a primary screen for candidate genes associated with AD.