180 Chapter 8 The general aim of this thesis was to study Alzheimer’s disease (AD) biomarkers in individuals with subjective cognitive decline (SCD). The first aim was to investigate the predictive value of biomarkers in the ATN classification, and the main findings were that ATN biomarker profiles were associated with cognitive decline and clinical progression to mild cognitive impairment (MCI) or dementia. The second aim was to explore the effects of using different definitions of abnormality of AD biomarkers. We found not only amyloid positivity, as defined by different thresholds, but also grey zone amyloid burden was associated with memory decline, or a diminished practice effect. With regard to the definition of neurodegeneration, we found biomarkers for N as obtained by different modalities correlated only moderately, suggesting they do not all reflect the same underlying pathology. The third aim was to evaluate factors associated with the longitudinal trajectories of AD biomarkers. We found multiple genes, combined in a polygenic risk score (PRS), were associated with amyloid positivity and clinical progression to AD dementia, independently of APOE ε4, a well-known risk factor. Furthermore, APOE ε4 carriership was not only associated with amyloid positivity, but also with an increase in amyloid burden over time and a higher risk of changing from a negative to positive status. We also investigated relative cerebral blood flow (rCBF) in relation to amyloid accumulation, and found that a high amyloid burden was associated with a subsequent decline in rCBF, but also vice versa, a low rCBF was associated with a subsequent increase in amyloid burden. Last, we found the order in which biomarkers in the ATN classification become abnormal is variable, which implies that not every individual follows the most generally accepted sequence of A → T → N. In the next sections, the findings of each chapter are summarized. Then, several methodological considerations of the studies that were conducted will be discussed. Last, clinical implications and future directions will be considered.