221 Longitudinal change in ATN biomarkers variability and could therefore be interpreted as more consistent. However, quantitative measures of amyloid burden are often averaged over a larger ROI. If a scan is visually assessed as A+ based on a relatively small area, this does not necessarily translate in a higher average BPND in the total ROI, which could be a potential cause of differences between the two approaches. Overall, we found a relatively high degree of changing biomarkers in a short time frame. These results add to the literature suggesting the clinical relevance of changing from a negative to a positive amyloid status. When we compared ATN profiles over time, we found 44% of individuals changed to a different ATN profile during 2.5 years of follow-up. Data on changing biomarkers enable the evaluation of the actual sequence of biomarker abnormality. Of note, most (11/17) individuals followed a different sequence than the overall accepted hypothesis of A becoming abnormal first, then T and N last [2]. In our sample, individuals changed to T+ or N+ while still being A− or changed to N+ before T+. These findings are in line with those of a former study investigating change in ATN profiles, which also found multiple sequences [5]. There are several possible explanations for these observations. First, amyloid could already be accumulating in the subthreshold range in individuals changing to T+ or N+, but before A+, suggesting the pathological process 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 [27]. 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, 28]. 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 [29–31], although not all [7, 32]. The relationship between ε4 carriership and a higher risk of change from A− to A+ has also been confirmed [9, 33]. 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, 30], we did not find a relationship between a lower baseline cognitive performance and subsequent amyloid accumula8
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