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Nature Research, Nature Genetics, 2(39), p. 168-177, 2007

DOI: 10.1038/ng1943

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

Journal article published in 2007 by Ekaterina Rogaeva, Yan Meng, Joseph H. Lee ORCID, Yongjun Gu, Toshitaka Kawarai, Fanggeng Zou, Taiichi Katayama, Clinton T. Baldwin, Rong Cheng, Hiroshi Hasegawa, Fusheng Chen, Nobuto Shibata, Kathryn L. Lunetta ORCID, Raphaelle Pardossi-Piquard, Christopher Bohm and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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