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Nature Genetics 39, 168–177 (1 February 2007) | doi:10.1038/ng1943

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

Ekaterina Rogaeva , Yan Meng , Joseph H Lee , Yongjun Gu , Toshitaka Kawarai , Fanggeng Zou , Taiichi Katayama , Clinton T Baldwin , Rong Cheng , Hiroshi Hasegawa , Fusheng Chen , Nobuto Shibata , Kathryn L Lunetta , Raphaelle Pardossi-Piquard , Christopher Bohm , Yosuke Wakutani , L Adrienne Cupples , Karen T Cuenco , Robert C Green , Lorenzo Pinessi , Innocenzo Rainero , Sandro Sorbi , Amalia Bruni , Ranjan Duara , Robert P Friedland , Rivka Inzelberg , Wolfgang Hampe , Hideaki Bujo , You-Qiang Song , Olav M Andersen , Thomas E Willnow , Neill Graff-Radford , Ronald C Petersen , Dennis Dickson , Sandy D Der , Paul E Fraser , Gerold Schmitt-Ulms , Steven Younkin , Richard Mayeux , Lindsay A Farrer & Peter St George-Hyslop

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 β peptide (Aβ) 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 Aβ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.