Amyloid Precursor Protein Sorting Does the Apolipoprotein E Genotype Influence Amyloid Precursor Protein Sorting by Sortilin‐related Receptor: Implications for Alzheimer's Disease?

The amyloid hypothesis of Alzheimer's disease (AD) argues that the cerebral accumulation of amyloid is a primary driver of AD pathology, including amyloid plaque deposition, neurofibrillary tangle formation, synapse loss and neuronal cell death. Many lines of evidence support this hypothesis, and some major players of the cascade have been identified, including the amyloid precursor protein (APP), apoliprotein E (APOE), the beta‐site APP cleaving enzyme (BACE1), and the sortilin‐ related receptor (SORL1). However, the processes that finally lead to amyloid accumulation are still poorly understood. Recent evidence suggests that SORL1 is able to switch away APP from the amyloidogenic cleavage by BACE1. It has also been suggested that SORL1 activity is influenced by its ligand APOE. Alterations in the three‐dimensional structure and in the binding properties of APOE related to the APOE4 genotype may cause changes in the interaction between SORL1 and APOE. These changes could affect the capacity of SORL1 to bind to APP, resulting in a reduced retention of APP by SORL1 in subcellular compartments. It appears promising to investigate possible associations between distinct single nucleotide polymorphisms within the SORL1 gene and the cerebrospinal fluid products of the amyloid cascade, and to test if these associations are modified by the APOE genotype. This may considerably enhance our understanding of the pathological processes leading to AD. † The first two authors contributed almost equally.