With the firm focus on increased levels of both soluble and insoluble Aβ in the brain and cerebrospinal fluid (CSF) in AD, relatively little attention has been given to a possible associated reduction in α-secretase activity and thus a shift away from the production of APPsα that might amplify the toxic effects of Aβ, hyperphosphorylated tau and other neuropathologies. Here, MAPT is linked to Alzheimer disease.