Conversely, in AD and all primary tauopathies, protein Tau becomes more and more phosphorylated with disease progression, to enter a state that is generally referred to as “hyper-phosphorylated.” Nevertheless, no exact lower or upper limits are defined to this connotation, which exposes a major molecular and analytical problem: how many of the vast number of potential O-phosphorylation sites in protein Tau are physiologically relevant? This evidence concerns the gene MAPT and Alzheimer disease.