A current challenge in Alzheimer disease (AD) research is to identify the sequence of pathologic changes that occurs during preclinical stages of disease in advance of cognitive decline. The timing of appearance of the 2 pathologic hallmarks of AD-amyloid deposition and tau-mediated neurodegeneration-is a particular topic of debate, with researchers drawing on a broad range of genetic, neuroimaging, fluid biomarker, animal, and autopsy studies to piece together the series of events ultimately leading to the plaques, neurofibrillary tangles, and cognitive deficits that define AD.