13 General introduction Although only the triad of amyloid, tau and neurodegeneration are represented in the ATN framework, other disease pathways might also play a role. In the ATN framework, for example, genetic risk factors are not addressed because they are no measure of pathology. However, the APOE gene has been associated with a higher rate of amyloid positivity and a higher risk of clinical progression, highlighting its relevance (34). In recent years, many other genes have been identified that likely play a role in the pathophysiology of AD, but these still need to be investigated in relation to AD biomarkers and clinical features (35). Furthermore, other processes such as changes in cerebral blood flow (CBF) are also suggested to play a role in the pathophysiology of AD (36, 37). With dynamic PET scans, it is possible to assess amyloid burden and CBF simultaneously in vivo, since it provides two unique parameters: binding potential (BPND) and R1. BPND is a measure of exact quantification of specific binding to amyloid-beta (38). R1 represents the ratio between the rate constant for ligand transfer from plasma to tissue (K1) in the target region and the reference region. This can be used as measure for relative CBF (rCBF) (39-41). CBF is shown to be abnormal in AD dementia and relates to changes in brain glucose metabolism and synaptic failure (42-44). It is currently unclear how CBF and other biomarkers such as amyloid burden are interrelated, especially in the early stages of the disease, as previous studies provide conflicting results and are hampered by small sample sizes (45-52). 1