The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein ( APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide ( A beta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late- onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene ( also known as LR11 or SORLA) may regulate tissue- specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into A beta- generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.