MAPT and Alzheimer disease: Over the past two decades, several clinical trials that have attempted to reduce Aβ production by decreasing β- or ɣ-secretase activity or directly targeting Aβ by immunotherapy did not meet pre-specified clinical endpoints in mild to moderate AD patients, perhaps due to the presence of well-established amyloid and tau neuropathology and the complexity of accessing the most pathogenic Aβ species.