This study investigates the relationship between tau pathology and clinical and neuroanatomical variability in Alzheimer's disease using the 18F-AV1451 PET tracer. The study included 20 patients with probable Alzheimer's disease dementia or mild cognitive impairment and 15 cognitively normal individuals. 18F-AV1451, 11C-PIB, and 18F-FDG PET scans were performed, along with APOE genotyping and neuropsychological testing. The results showed that 18F-AV1451 patterns in patients with posterior cortical atrophy (PCA) targeted clinically affected posterior brain regions, while 11C-PIB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation showed highest 18F-AV1451 retention in medial temporal and lateral temporoparietal regions, and patients with logopenic variant primary progressive aphasia demonstrated asymmetric left greater than right hemisphere 18F-AV1451 uptake. Across 30 regions of interest in 16 Alzheimer's disease patients, there was a strong negative association between 18F-AV1451 and 18F-FDG uptake, and less pronounced positive associations between 11C-PIB and 18F-FDG, and 18F-AV1451 and 11C-PIB. Younger age was associated with greater 18F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased 18F-AV1451 in the medial temporal lobe. APOE ε4 carriers showed greater temporal and parietal 18F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater 18F-AV1451 uptake in key regions implicated in memory, visuospatial function, and language. These findings suggest that tau imaging shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease, consistent with findings from post-mortem, animal, and CSF studies.This study investigates the relationship between tau pathology and clinical and neuroanatomical variability in Alzheimer's disease using the 18F-AV1451 PET tracer. The study included 20 patients with probable Alzheimer's disease dementia or mild cognitive impairment and 15 cognitively normal individuals. 18F-AV1451, 11C-PIB, and 18F-FDG PET scans were performed, along with APOE genotyping and neuropsychological testing. The results showed that 18F-AV1451 patterns in patients with posterior cortical atrophy (PCA) targeted clinically affected posterior brain regions, while 11C-PIB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation showed highest 18F-AV1451 retention in medial temporal and lateral temporoparietal regions, and patients with logopenic variant primary progressive aphasia demonstrated asymmetric left greater than right hemisphere 18F-AV1451 uptake. Across 30 regions of interest in 16 Alzheimer's disease patients, there was a strong negative association between 18F-AV1451 and 18F-FDG uptake, and less pronounced positive associations between 11C-PIB and 18F-FDG, and 18F-AV1451 and 11C-PIB. Younger age was associated with greater 18F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased 18F-AV1451 in the medial temporal lobe. APOE ε4 carriers showed greater temporal and parietal 18F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater 18F-AV1451 uptake in key regions implicated in memory, visuospatial function, and language. These findings suggest that tau imaging shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease, consistent with findings from post-mortem, animal, and CSF studies.