Correlation of Alzheimer Disease Neuropathologic Staging with Amyloid and Tau Scintigraphic Imaging Biomarkers

PET neuroimaging of amyloid-β (Aβ) provides an in vivo biomarker for pathologic changes associated with Alzheimer disease (AD). Aβ-targeted agents have been approved by the Food and Drug Administration, with additional agents, most notably targeting tau, currently under clinical investigation and one approved in May 2020. These agents, along with nonscintigraphic biomarkers from blood and cerebrospinal fluid, have provided an opportunity to investigate the pathogenesis, prodromal changes, and time course of the disease in living individuals. The current understanding is that the neuropathologic changes of the AD continuum begin up to 25 y before the onset of clinical symptomatology. The opportunities afforded by in vivo biomarkers of AD, whether by serum, cerebrospinal fluid examination or PET, have transformed the design of AD therapeutic trials by shifting focus to the preclinical stages of disease. Future disease-modifying therapies, should they be forthcoming, will rely heavily on the use of approved biomarkers or biomarkers currently under investigation to confirm the presence of target pathology. Understanding the progressive neuropathologic changes that occur in AD-and how scintigraphic findings relate to these changes-will help the interpreting physician to fully appreciate the implications of the scintigraphic findings and provide a basis to interpret the examinations. The recently adopted National Institute on Aging-Alzheimer Association guidelines define postmortem AD neuropathologic changes as a composite score based on 3 elements. These elements are the extent of involvement (spread) by cerebral Aβ based on the progression model defined by the Thal Aβ phases, the extent of involvement (spread) by neurofibrillary tangles (composed of hyperphosphorylated tau proteins) based on the progression model defined by Braak, and the Consortium to Establish a Registry for Alzheimer's Disease score, which describes the density of neuritic plaques based on certain key locations in the neocortex. This paper will review the 3 elements that define the National Institute on Aging-Alzheimer's Association scoring system and discusses current evidence on how these elements relate to findings based on Aβ and tau PET scintigraphy.