Our understanding of the relationship between brain amyloid and Alzheimer disease (AD) seems to be becoming murkier as we learn more about amyloid in vivo. Classic neuropathologic writings—when our understanding of AD was in its infancy—suggested that amyloid plaques and neurofibrillary tangles were the hallmark features of AD. This belief became formalized when the definition of AD was based on autopsy-confirmed findings of plaques and tangles exceeding a particular concentration. As in vivo imaging techniques developed that allowed us to identify potential biomarkers for AD, we began to test the effect of amyloid and tangles on the brain. Researchers using structural MRI have identified the strong linkage between cerebral cortical volume and burden of neurofibrillary tangles. Much like neuropathology studies, initial work was devoted to testing the hypothesis that reductions in brain regional volumes could be found in patients with AD compared to groups of healthy control subjects. To address the concern that reduced volumes might bear an incidental relationship rather than a causative one to the clinical state, attention turned to …