Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain

To identify SORL1 risk genotypes that determine receptor protein expression in the human brain.

DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively.

Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank.

Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease.

Our studies identified a SORL1 haplotype in the 3' gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein.

Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.