111 Tau PET and cognition in early- and late onset AD INTRODUCTION Alzheimer’s disease (AD) is characterized by depositions of amyloid-β plaques and hyperphosphorylated tau tangles[1]. The symptoms of AD are heterogeneous, partly related to age-at-onset. Late-onset AD is primarily associated with amnestic problems, while non-amnestic symptoms are more prominent when the disease manifests at younger age[2-6]. Atypical cognitive profiles in early-onset AD patients have previously been linked to specific spatial patterns of hypometabolism, atrophy, and more recently, tau pathology, that primarily affect the neocortex with relative sparing of the medial temporal lobe[7-10]. Age-at-onset is thus closely related to both cognitive symptoms and distinct patterns of tau pathology in AD. However, despite the notion that tau pathology is tightly linked to the degree of cognitive impairment in AD[11-17], it is currently unknown whether the association between tau pathology and cognitive performance is affected by age-at-onset. To address this question, we conducted a dynamic [18F]flortaucipir PET study. The dynamic scan protocol additionally yields a measure of R1. R1 represents the rate constant for ligand transfer from blood to tissue (K1) in the target region relative to the reference region, and can be interpreted as a proxy of relative cerebral blood flow [rCBF][18-24]. Several studies have demonstrated strong correlations between R1 and metabolic activity as measured with [ 18F]FDG PET[19, 20, 24, 25]. Furthermore, in a previous study, we showed that [18F]flortaucipir R1 is strongly associated with cognitive performance in AD, (partly) independently of tau pathology[17]. We therefore also investigated differences in rCBF and its association with cognitive performance, taking into account age-at-onset. Accordingly, we aimed to investigate the differences between early-onset AD and late-onset AD in 1) tau pathology and rCBF, and 2) the associations between tau pathology and rCBF with cognitive performance. We hypothesized that, relative to late-onset AD, early-onset AD displays higher levels of tau pathology. As R1 is tightly linked to hypometabolism measured with FDG-PET[19, 20, 24, 25], and lower levels of metabolism have previously been reported in early-onset AD patients, we expected to find lower levels of R1 in early- vs late-onset AD. Furthermore, as early-onset AD may represent a more ‘pure’ form of AD with relatively few comorbidities compared to late-onset AD[26], we hypothesized that tau pathology and cognitive performance would be more strongly associated in early- vs late-onset AD. 5
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