The Sortilin-Related Receptor SORL1 is Functionally and Genetically Associated with Alzheimer's 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 P-peptide (A beta), the accumulation of which is thought to be central to the pathogenesis of Alzheimer's disease (AD). Inherited variants in the SORL1 neuronal sorting receptor have been reproducibly associated with late-onset AD. These variants occur in intronic sequences and may regulate tissue-specific expression of SORL1, which directs trafficking of APP into recycling pathways. When SORL1 is under-ex pressed, APP is sorted into A beta-generating compartments. These data lead to the conclusion that inherited or acquired changes in SORL1 gene expression or function are mechanistically involved in causing AD.