39 ATN classification in subjective cognitive decline DISCUSSION In a sample of individuals with SCD presenting at a memory clinic, we found that Alzheimer’s continuum profiles (A+T-N-, A+T-N+, A+T+N-, A+T+N+) together make up one fifth, and non-AD pathologic change profiles (A-T-N+, A-T+N-, A-T+N+) one third of cases. Most frequent is the profile with all biomarkers normal, observed in more than half of participants. Compared to A-T-N-, participants in A+ profiles were at increased risk of dementia and showed a steeper subsequent cognitive decline over the years on tests for memory, attention and executive functioning. Participants in A-T+N+ showed steeper decline on two memory tests, but other A- profiles were comparable to A-T-N- in terms of their cognitive trajectories. We extend on former findings by longitudinally evaluating the ATN-model in a population of cognitively normal individuals with SCD. In this clinically relevant population of individuals with SCD, particularly the A+ profiles defined in the ATNmodel have predictive value in terms of risk of future dementia and rate of cognitive decline, while not all profiles were sufficiently populated to warrant reliable risk estimates. This illustrates that biomarker information helps to identify those at risk, but also shows that the eight different profiles as defined in the ATN model are somewhat difficult to implement. We therefore supplemented our results with a more robust categorization in three clustered ATN categories (normal AD biomarkers; Alzheimer’s continuum); Non-AD pathologic change). The results of the analyses using the three clustered categories confirm that of all biomarkers assessed, especially the ‘A’ biomarker is strongly associated with clinical progression and cognitive decline. We found an uneven distribution of ATN profiles. This observation is largely consistent with former studies in nondemented individuals, although the exact prevalence of specific profiles somewhat differs between studies (2-4, 6, 7). Compared to earlier studies, most noteworthy is that more than half of our participants in both the SCD and control group were negative for all biomarkers (respectively 56% and 57%), while other studies found a much lower prevalence (29-39%) (2, 6, 7). On the other end of the profile spectrum, we found a very low prevalence of A+T+N+ in our SCD sample (2%), while other studies found higher percentages (9-12%) (2, 6, 7). The fact that our SCD sample is 10-15 years younger than other cohorts and was carefully selected to be cognitively normal at baseline probably explains this effect and explains our apparently lower amyloid rate, as age has been shown to play a huge role in biomarker positivity (2, 44, 45). At the same time, our results show that in this population, the observation of amyloid is not benign, as it is strongly associated with future dementia. Additionally, discrepancies with other studies can be explained 2
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