© 2016 The Author. The advent of the positron emission tomography tracer18F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent18F-AV1451 (tau),11C-PiB (amyloid-β) and18F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that18F-AV1451 and18F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while11C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest18F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere18F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between18F-AV1451 and18F-FDG uptake (Pearson's r =-0.49 ± 0.07, P < 0.001) and less pronounced positive associations between11C-PiB and18F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and18F-AV1451 and11C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater18F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased18F-AV1451 in the medial temporal lobe. APOE Ïμ 4 carriers showed greater temporal and parietal18F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater18F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.