119 Risk of dementia related to APOE ε4 and a polygenic risk score Limitations of our study include that the sample size in some ATN profiles was rather small. However, the three clustered ATN categories provided similar results which confirms robustness of the findings. Furthermore, we based our PRS on current knowledge, but with increasing numbers of genetic studies, the number of variants in the PRS will also change. Comparing results across studies is complicated by the fact that each study uses a slightly different PRS. Using a more liberal threshold for inclusion of genetic variants in the PRS could lead to a higher disease prediction accuracy, however, an extremely liberal approach could also lead to the inclusion of non-informative SNPs which limits discrimination ability (55-57). In our PRS, we adopted a conservative approach and included only 39 genetic variants with genome-wide significant evidence of association with AD. Also, the results might not be directly generalizable due to the fact that our population included solely individuals of European descent. Additionally, although the follow-up duration in our study was relatively long, the conversion rates were low, as is expected in a cognitively normal population. It is important to note that the differences in conversion to dementia became apparent only after 3-4 years of follow-up. With a longer follow-up duration, the predictive value of genetic variants becomes more evident. Strengths of our study include that we have biomarker data used to define ATN categories in a large population of cognitively normal individuals. Individuals of the current study all presented at our memory clinic worrying about their memory and requesting information on likelihood of dementia in the future, which adds to the clinical relevance of our results. Our results are on a group level, but provide proof of principle that in the future, genetic information may inform individualized risk profiling. Furthermore, we tested the association between genetic variants and biomarkers using the ATN classification system, which has not been done before. With this approach, we used A-T-N- as a reference in our analyses, which enabled us to detect more specific associations than other studies that used a broader amyloid negative group as a reference, because this group could also include tau pathology or neurodegeneration. In conclusion, we found that an AD-specific PRS is associated with AD biomarkers, particularly amyloid positivity, independent of APOE ε4 in cognitively normal elderly. In addition, both PRS and APOE ɛ4 were associated with risk of AD dementia, in such a way, that a low PRS attenuated the detrimental effect of APOE ε4. This could have implications for the selection of participants for trials, risk stratification, and personalized medicine. Genetic variants other than APOE should not be ignored, because they have a relevant contribution to the disease. 5