172 Chapter 7 has started just below the detection threshold. An alternative explanation is the suggestion of the dual-pathway hypothesis, in which amyloid and tau accumulation are both the result of a common upstream event, not necessarily causally related to each other (23). Finally, there could be mixed pathology, resulting in N+ due to other diseases than AD, hence not related to a specific ordering of events. Overall, the number of individuals with the A-T-N- profile became smaller and the number of individuals with non-AD pathologic change (A-T+N-, A-T-N+, A-T+N+) became larger at follow-up. In a previous study by our group, but also in other studies, these profiles did not have a higher risk of cognitive decline or clinical progression to MCI or dementia (3, 24). When we evaluated determinants of change to amyloid positivity, we found APOE ε4 carriers had a higher baseline amyloid burden, a higher risk of transition from A- to A+ and a higher annual amyloid accumulation rate. Several studies confirm a relationship between ε4 carriership and a higher accumulation rate (25-27), although not all (7, 28). The relationship between ε4 carriership and a higher risk of change from A- to A+ has also been confirmed (9, 29). We add to these results with the finding that ε4 carriership is also associated with risk of change in a sample of cognitively normal individuals with SCD. We did not find evidence for an association with any of the other factors examined, such as baseline age, sex or education level. In apparent contrast with former studies (9, 26), we did not find a relationship between a lower baseline cognitive performance and subsequent amyloid accumulation. Reasons for this inconsistency could be that an inclusion criterion for our study is normal performance at baseline and that variability in baseline cognition is small. Therefore, relationships with amyloid accumulation may be obscured. In short, our results suggest A- individuals who are ε4 carrier are still at risk of progression to A+. Limitations of our study include that although repeated measures of amyloid were available for an adequate sample, a full ATN profile at baseline and follow-up was only available for a subset. Furthermore, we used [18F]flortaucipir PET as measure of tau burden. We pragmatically used Gaussian Mixture Modelling of [18F]flortaucipir to obtain a threshold, although there might be other approaches. Nevertheless, our approach resulted in a percentage of T+ which lies within the range of T+ described in other studies in cognitively normal individuals (3, 30-32). Of note, during the recruitment of individuals for the [18F]flortaucipir PET scan, we slightly oversampled A+ individuals. Because substantial tau pathology within A- cognitively normal individuals is not expected to be present, we selected more A+ individuals for the [18F]flortaucipir PET in order to have a broader spectrum of amyloid and tau pathology. Therefore, our results might not reflect the true prevalence of amyloid and tau pathology in
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