118 Chapter 5 We found that a high AD PRS was associated with abnormal amyloid status and a higher risk of AD dementia. Former studies provided contradictory results about the relationship between the PRS and amyloid status. Discrepancies could be related to differences in disease stage, since amyloid positivity rates differ regarding diagnostic status. Furthermore, some studies found an association between a PRS without APOE and amyloid burden (15, 42-44), but in others the association was lost when APOE was not included in the PRS (14, 16, 45, 46). Similarly, literature is inconsistent about the relationship between the PRS and risk of AD dementia (11-13, 47-50). Differences could be explained by of the use of different populations, since studies that reported no increased risk of clinical progression used an MCI population (47), and others reported lower hazard ratios for MCI individuals compared to cognitively normal individuals (13, 50). Furthermore, the PRSs are not directly comparable, since a different number of SNPs is included in the different PRSs. The relationship between APOE and amyloid status has been firmly established (7, 14, 51). We extend on those findings by showing not only an association between APOE and amyloid status, but also between APOE and tau status. As amyloid burden and p-tau are closely related, the relationship between APOE and p-tau could either be mediated through amyloid burden, or be amyloid independent. We found that APOE ε4 carriers have higher odds of being A-T+N- compared to A-T-N-. In line with literature, this suggests the additional involvement of amyloid-independent pathways (52-54). Overall, our results provide evidence for the concept that genetic variants beyond APOE are associated with amyloid status, which is the crucial pathophysiological processes underlying AD. The risk of dementia associated with APOE and the PRS seemed to be additive, as individuals with both an ε4 allele and a high PRS had the highest risk of progression to AD dementia. In line with literature, carriers of the ε4 allele with a low PRS, or non-carriers with a high PRS, had substantially lower risks. This implies that the genetic risk of AD dementia can be more accurately estimated when in addition to APOE, also non-APOE genetic variants are considered. To date, genetic information, including APOE status is not used for risk profiling in a clinical setting. Although it has been established that the ε4 allele is associated with a higher risk of dementia on a group level, these data do not easily translate to the individual, as not all ε4 carriers will develop dementia, while conversely also individuals without ε4 can develop dementia. We showed that taking into account all genetic variants associated with AD results in more accurate estimates of future AD dementia. In the future, taking into account ones’ genetic risk of AD could have clinical relevance, especially for individuals who present with worries about their memory at a memory clinic.