14 Chapter 1 Aim and thesis outline In this thesis we studied the value of AD biomarkers for predicting clinical progression in SCD. More specifically, we aimed to: 1. Investigate the predictive value of biomarkers in the ATN classification by assessing the associations with cognitive decline and risk of clinical progression to MCI or dementia. 2. Explore the effects of different definitions of abnormality of AD biomarkers 3. Evaluate factors underlying the trajectories associated with AD biomarker abnormalities In chapter 2, we addressed the first aim by using the ATN classification to investigate the joint value of amyloid PET or CSF abeta (A), CSF p-tau (T) and medial temporal atrophy (N) on MRI. We investigated the relationship with cognitive decline and clinical progression. Chapters 3 and 4 address the second aim. In chapter 3 we explored how different thresholds for amyloid positivity based on amyloid burden on [18F]florbetapir PET relate to cognition and considered the possibility of a grey zone. In chapter 4 we used different modalities to define neurodegeneration and investigated the added value of each definition beyond amyloid-beta and p-tau. Chapters 5, 6 and 7 address the third aim. In chapter 5, we investigated the relationship between ATN biomarkers, the APOE gene and a polygenic risk score, and their association with clinical progression to dementia. In chapter 6, we investigated the relationship between the longitudinal trajectories of amyloid burden on PET and a measure of relative cerebral blood flow. Last, in chapter 7, we investigated longitudinal change in ATN classification and amyloid status.