Retromer sorting - A pathogenic pathway in late-onset Alzheimer disease

During the tail end of the 20th century, a golden period in Alzheimer disease ( AD) research, many of the pathogenic molecules of the autosomal dominant form of the disease were isolated. These molecular defects, however, do not exist in sporadic late-onset AD, the form of the disease that accounts for more than 95% of all cases. Pinpointing the pathogenic molecules of late-onset AD has, therefore, become an urgent goal, both for understanding disease mechanisms and for opening up novel therapeutic avenues. The retromer sorting pathway transports cargo along the endosome-trans-Golgi network, and retromer defects were first implicated in late-onset AD by a study that combined brain imaging with microarray. A range of studies have confirmed that defects in this pathway can play a pathogenic role in the disease. Herein, these findings will be reviewed, the details of the retromer sorting pathway will be discussed, and a biological model that can account for the disease's regional selectivity will be elaborated.