Late‐onset AD risk mutation PICALMH458R prevents plaque generation in 5xFAD mice

To understand the processes that drive late‐onset Alzheimer’s Disease (AD), genome‐wide association studies (GWAS) have uncovered many risk loci. One of these is within the phosphatidylinositol‐binding clathrin assembly protein (PICALM) gene, and a coding mutation has been identified (H458R) which conveys increased risk. PICALM is a cytosolic protein involved in regulating the formation of the lattice during endocytosis. The role of PICALM in AD has not fully defined, however, there are several reports indicating that PICALM affects AD risk primarily by modulating the production, transportation, and clearance of Aβ.