40 Chapter 2 by their defining both T and N based on CSF (p-tau and total tau). Due to the high correlation between these two measures (also shown in the current study), profiles like A+T+N- and A-T+N- become highly improbable when both T and N are defined based on CSF. When this approach was chosen, none of the participants falls into these mutually exclusive profiles (3). In our study, we used CSF p-tau to define T and MRI-based medial temporal lobe atrophy for N, because they are both widely available and clearly measure different aspects of the disease as evident by the fact that both categories were populated by a considerable fraction of the sample (A-T+N-: 19.8%; A-T-N+: 5.6%). When we compare our SCD sample to our own control group without SCD, we found a larger number of participants that were positive for N in our control group, resulting in different percentages in A-T-N+ (6% versus 17%) and A-T+N- (20% versus 10%). In addition, A+ seemed somewhat less prevalent in the controls than in SCD (14% vs 18%), particularly when taking into account that controls were older than individuals with SCD. It should be noted our study was not designed to study the effect of SCD on risk of progression, but rather to evaluate the clinical usefulness of ATN profiles in this clinically relevant population. Adding SCD as an additional factor to the ATN scheme (‘ATN-S’) would increase the number of categories even more, and our current results show that the high number of categories is already a limitation to the clinical applicability of the ATN scheme. We observed that participants in three A+ profiles showed a faster cognitive decline over the years on tests for memory, attention and executive functioning. This is largely in line with a study conducted by the Mayo clinic, that found especially A+T+N-, A+T-N+ and A+T+N+ show a steeper decline on memory tests compared to A-T-N- (6). Another study found that only A+T+N+ had a greater decline on a cognitive factor score (7). Our results provide further support for the observation that effect sizes of cognitive decline seem to increase with the number of biomarkers affected. We found participants in A+ profiles to be at increased risk of dementia. Of note, within the three A+ profiles, we observed risk estimates to increase with the number of biomarkers affected, illustrating the added value of having biomarker information on all three biomarkers available, and – conversely - that lumping all A+ profiles together may obscure differences in outcomes of the different biomarker categories. The two previous longitudinal studies investigating ATN in cognitively unimpaired participants assessed cognitive trajectories, but did not assess risk of clinical progression to MCI or dementia (6, 7). There is only one longitudinal study evaluating the risk of dementia associated with the ATN classification, using an MCI sample, that found amyloid positivity was associated with a higher risk of dementia (5). In addition, we also found a higher risk of dementia in A-T+N+. The A-T+N+ category contained only