Biochemical, phosphoproteomic, electrophysiological, and behavioral studies revealed that elevated PKC activity conferred by the presence of this AD variant leads to increased phosphorylation of PKC substrates in the brain, neurite degeneration, enhanced Aβ driven synaptic depression, and cognitive decline, which is more evident and more rapid on the background of a transgenic mouse model of AD. This evidence concerns the gene PRRT2 and Alzheimer disease.