In Vivo Cortical Spreading Pattern of Tau and Amyloid in the Alzheimer Disease Spectrum

Objective: To determine the in vivo cortical spreading pattern of tau and amyloid and to establish positron emission tomography (PET) image-based tau staging in the Alzheimer disease (AD) spectrum. Methods: We included 195 participants (53 AD, 52 amnestic mild cognitive impairment [MCI], 23 nonamnestic MCI, and 67 healthy controls) who underwent 2 PET scans (F-18-florbetaben for amyloid-beta and F-18-AV-1451 for tau). We assumed that regions with earlier appearances of pathology may show increased binding in a greater number of participants and acquired spreading order of tau accumulation by sorting the regional frequencies of involvement. We classified each participant into image-based tau stage based on the Z score of the composite region for each stage. Results: Tau accumulation was most frequently observed in the medial temporal regions and spread stepwise to the basal and lateral temporal, inferior parietal, posterior cingulate, and other association cortices, and then ultimately to the primary cortical regions. In contrast, amyloid accumulation was found with similar frequency in the diffuse neocortical areas and then finally spread to the medial temporal regions. The image-based tau stage correlated with the general cognitive status, whereas cortical thinning was found only in the advanced tau stages: medial temporal region in stage V and widespread cortex in stage VI. Interpretation: Our PET study replicated postmortem spreading patterns of tau and amyloid-beta pathologies. Unlike the diffuse accumulation of amyloid throughout the neocortex, tau spreading occurred in a stepwise fashion through the networks. Image-based tau staging may be useful for the objective assessment of AD progression.