222 Chapter 8 tion. 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 our sample size was relatively small. With a larger sample size, our study would have had more power to detect more subtle determinants of changes in A status. The results of our analyses examining changing amyloid status as predictor of cognitive decline should also be interpreted with caution and replicated in larger samples. Furthermore, we used [18F]flortaucipir PET as measure of tau burden. We pragmatically used Gaussian mixture modeling 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, 34–36]. 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 cognitively normal individuals and the results might not be directly generalizable to the general population. Another factor that potentially impacts generalizability is the fact that the individuals in our sample were mainly recruited at a memory clinic. Strengths include the longitudinal nature of the study with the availability of biomarkers, diagnoses, and cognition with substantial duration of follow-up. Furthermore, we used dynamic scan protocols which enabled us to calculate BPND, which is a more accurate measure of amyloid and tau load than the semi-quantitative SUVr. Another strength is our use of [18F]flortaucipir for the definition of “T,” since it does not suffer from off-target binding to amyloid plaques or TDP-43 and correlates well with Braak neurofibrillary tangle stages [37]. Concluding, we showed biomarker status changes in cognitively normal individuals with SCD. There was considerable variability in the sequence of ATN biomarkers becoming abnormal, suggesting that there is not one (causal) order of events. Changing from a negative to positive amyloid status was associated with APOE ε4 carriership and predicted subtle cognitive decline, suggesting the potential clinical relevance of amyloid burden in the negative range.
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