Meta-analysis of the Association Between Variants in SORL1 and Alzheimer Disease

Abstract

The neuronal sortilin-related receptor gene (SORL1) is a susceptibility gene for late-onset Alzheimer disease (AD),^1-7 is located on chromosome 11q23.2-q24.2, and encodes a 250-kDa membrane protein expressed in neurons of the central and peripheral nervous system.⁸ The biological evidence for a role of SORL1 in AD is compelling: SORL1 is part of the VPS10 vacuolar protein–sorting receptor family,^9,10 which in turn belongs to a group of protein-trafficking molecules in the endocytic and retromer pathways.^9,10 These subcellular domains are important sites for the generation of the amyloid β–peptide (Aβ), the main putative culprit in AD. In patients with AD and persons with the amnesic form of mild cognitive impairment, an early stage of AD, the expression of SORL1 is reduced in neurons but not glia in the brain.^11,12 However, this reduction is not a consequence of AD because SORL1 expression is not altered in patients with presenilin 1 mutations.^11,12 Cell biological experiments suggest that underexpression of SORL1 modulates amyloid precursor protein processing, leading to overproduction of Aβ.⁶