How Variants in The SORL1 Gene, Encoding an Endosome Sorting Receptor, Can Cause Alzheimer’s Disease

The SORL1 gene encodes an intracellular sorting receptor with an important role in the endosome recycling pathway of cargo in several different cell types of the brain, including transport of Glutamate receptors back to the plasma membrane and escorting the Amyloid precursor protein away from amyloidogenic processing in neurons. Accordingly, when defects in SORL1 activity is modeled in hiPSC-derived neurons and animal models including mice and minipigs, these models display several of the cardinal phenotypes and pathological hallmarks of patients with Alzheimer’s disease.
SORL1 is now considered a causal gene for Alzheimer’s disease, originally guided by the group of loss-of-function genetic mutations that almost exclusively is found among patients with Alzheimer’s disease in case-control exome sequencing studies. However, more recently a steadily increasing number of genetic missense variants in SORL1 is now also considered pathogenic, and using a number of cell-based assays it has recently been possible to provide functional data in support how pathogenic variants can be identified. Thus, SORL1 is a strong genetic factor the can influence the development of neurodegeneration, but also holds certain promises as a target for therapeutic intervention.