Given the unclear relationship between established CSF tau biomarkers and NFT burden [32, 33], increases in P-tau181p and T-tau levels may in fact reflect increased tau secretion resulting from the spread of AD-affected cells at risk of tangle pathology [34], with increases in tau-368 levels reflecting an expansion in the pool of C-terminal fragments, possibly due to increased cleavage activity. This evidence concerns the gene MAPT and Alzheimer disease.