Research into Alzheimer's disease pathology and treatment has often focused on 
presenilin proteins. These proteins provide the key catalytic activity of the 
γ-secretase complex in the cleavage of amyloid-β precursor protein and resultant 
amyloid tangle deposition. Over the last 25 years, screening novel drugs to 
control this aberrant proteolytic activity has yet to identify effective 
treatments for the disease. In the search for other mechanisms of presenilin 
pathology, several studies have demonstrated that mammalian presenilin proteins 
also act in a non-proteolytic role as a scaffold to co-localize key signaling 
proteins. This role is likely to represent an ancestral presenilin function, as 
it has been described in genetically distant species including non-mammalian 
animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from 
the human lineage over a billion years ago. Here, we review the non-catalytic 
scaffold role of presenilin, from mammalian models to other biomedical models, 
and include recent insights using Dictyostelium, to suggest that this role may 
provide an early evolutionary function of presenilin proteins.