147 Cerebral blood flow, amyloid burden and cognition DISCUSSION In this study in a relatively large sample of cognitively normal individuals, we found that low rCBF and high amyloid burden, both measured by dynamic [18F]florbetapir PET, were independently associated with worse trajectories for tests of memory and attention. Longitudinal imaging showed that despite absence of cross-sectional associations, higher baseline amyloid burden was associated with a decline in rCBF over time, while at the same time a low baseline rCBF was associated with increase in amyloid burden over time. This provides evidence that amyloid accumulation and reduced rCBF are parallel disease processes without fixed order in the cascade of events leading to cognitive decline. We found that low baseline rCBF predicted worse performance over time on tests for memory and attention. After adding baseline amyloid burden as covariate, rCBF remained associated with cognitive slope. For one memory test, there seemed to be an interaction effect, as rCBF predicted cognitive slope mainly in individuals with low amyloid burden. Our results are in line with previous studies that showed low baseline CBF predicted future cognitive decline (22, 23), and clinical progression to MCI or dementia (37, 38). We extend on these findings by showing rCBF adds unique predictive value in addition to amyloid burden, using an extensive neuropsychological test battery. Previous studies with a cross-sectional design found that lower baseline CBF was associated with worse concurrent cognitive performance in the entire disease spectrum (8, 10, 13, 39), but studies specifically investigating cognitively normal individuals report conflicting results (19, 21). We did not find any crosssectional associations between baseline rCBF and cognition. This is probably due to the fact that to be included in the SCIENCe project, our participants were extensively tested and judged to be cognitively normal, so variability in cognition at baseline is limited. This further highlights the importance of a longitudinal design with sufficient follow-up to study how brain changes contribute to cognitive decline in the earliest disease stages. When we evaluated rCBF and amyloid burden longitudinally, the two measures were clearly associated, as high baseline amyloid burden was associated with a decline in rCBF, while vice versa, a low baseline rCBF was associated with an increase in amyloid burden. There are a number of possible explanations for these observations. According to the amyloid cascade hypothesis, and as translated to living humans in the hypothetical biomarker model, amyloid accumulation is among the first changes related to AD. This subsequently leads to tau deposition and then to neuronal injury. When we interpret rCBF as a measure of neuronal injury, this should 6