The finding that antibodies recognising pathological forms of tau are not specific for the detection of NFTs, but also stain the cytoplasm in neurons devoid of NFTs [128,129,130,131], and the fact that PHF tau could be readily extracted from AD brain tissue using detergent-free buffers, suggested that pathological phosphorylation of tau represents an early event in the cascade of PHF and NFT formation [130,131,132], and provided a rationale for its detection in the CSF early in the disease course [129]. This evidence concerns the gene MAPT and Alzheimer disease.