AbstractBackgroundPositron emission tomography (PET) imaging enables the in vivo detection of amyloid and tau pathologies. The longitudinal progression of [18F]‐flortaucipir PET imaging could be of interest to better understand the spatial and temporal relationships between tauopathy, cortical atrophy, and the cognitive decline.MethodWe explored the longitudinal progression of the tau radiotracer binding and of cortical atrophy over 2 years in a cohort of 27 prodromal/mild AD patients (positive CSF biomarkers and amyloid‐PET) compared with twelve amyloid‐negative controls. All subjects underwent a complete neuropsychological assessment, 3T brain MRI, [11C]‐PiB and [18F]‐flortaucipir PET imaging (Tau1), and were monitored annually over 2 years, with a second brain MRI and tau PET imaging (Tau2) after 2 years. We studied the longitudinal progression of tau radiotracer binding (Tau2‐Tau1) in AD patients and used mixed effects models to explore the relations between the progression of tau binding or cortical atrophy and cognitive decline.ResultWe found an average longitudinal increase in tau radiotracer binding in most cortical regions, especially in the frontal cortex, but an average decrease in the lateral temporoparietal cortex. In this region, individual analyses revealed two distinct evolutions of tau radiotracer binding according to Tau1 uptake: low‐Tau1 AD patients (SUVr<1.6) demonstrated an increase in tau radiotracer uptake in all cortical regions and a slow clinical progression, whereas high‐Tau1 patients demonstrated a paradoxical plateauing or decrease of tau tracer uptake in the temporoparietal cortex and a faster clinical progression. Cognitive decline was weakly associated with Tau2‐Tau1, but strongly associated with the regional cortical atrophy progression.ConclusionOur results suggest that tau PET imaging could detect patients with a “more aggressive” biological form of AD characterized by high temporo‐parietal Tau1 binding. In these patients, the decrease of temporo‐parietal tau tracer binding over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. This information may be considered to improve the design of clinical trials and the definition of the neuroimaging outcomes (choice of the tau‐PET regions of interest, consideration of the evolution of cortical atrophy as a reliable reflection of the clinical progression).