133 Cerebral blood flow, amyloid burden and cognition INTRODUCTION Deposition of amyloid β (Aβ) into plaques is one of the main pathophysiological hallmarks of Alzheimer’s disease (AD) (1). According to the amyloid cascade hypothesis, amyloid accumulation is the primary event in the pathogenesis of AD and initiates a series of events that ultimately result in neuronal damage and dementia (2, 3). The process of amyloid accumulation starts decades before the onset of dementia, and amyloid plaques can already be present in cognitively normal individuals (4). Although amyloid pathology is an important marker of AD, other pathological processes also play a role, such as tau pathology, neuroinflammation and changes in cerebral blood flow (CBF). Indeed, CBF is shown to be abnormal in AD dementia and relates to changes in brain glucose metabolism and synaptic failure (5-7). Several studies using measures of CBF such as arterial spin labelling (ASL) MRI, early phase amyloid PET or [15O]H 2O PET found a lower CBF to be associated with advancing disease stage (8-13). It is currently unclear how CBF and amyloid burden are interrelated, especially in the early stages of the disease, as previous studies provide conflicting results and are hampered by small sample sizes (11, 14-20). In addition, most studies used a cross-sectional design, precluding the investigation of longitudinal trajectories. Only one study investigated CBF longitudinally and found both increases and decreases in CBF in amyloid positive individuals (15). CBF has furthermore been shown to be associated with cognition, but studies provide conflicting results and longitudinal studies are scarce (21-23). Amyloid burden and CBF can be assessed simultaneously in vivo with dynamic [18F] florbetapir PET scans. Dynamic scanning provides two unique parameters of interest: (i) binding potential (BPND), which is an exact quantification of specific binding to Aβ (24), and (ii) R1, which represents the ratio between K1 (the rate constant for ligand transfer from plasma to tissue) in the target region and the reference region, and which can be seen as a measure for relative CBF (rCBF) (9, 25, 26). As a result, one [18F]florbetapir PET scan provides quantitative information on both amyloid load and rCBF. This study focused on cognitively normal individuals who experienced cognitive complaints. These individuals presented to a memory clinic which makes them a clinically relevant population to study early amyloid pathology and the role of rCBF in the development of AD pathology. The aims of this study were (1) to assess the association between amyloid burden, rCBF and cognitive decline over time and (2) to investigate the relationship between (rate of accumulation of) amyloid burden and (rate of change in) rCBF in a relatively large sample of cognitively normal individuals. 6