10 Chapter 1 a syndrome to a biological construct. Each individual can be rated for the presence of abnormal amyloid-beta (A), hyperphosphorylated tau (T) and neurodegeneration (N), resulting in eight possible biomarker combinations, or ATN profiles. According to the ATN framework, individuals have AD when they have abnormal values for both amyloid and tau. Individuals with abnormal values for only amyloid are assigned the label Alzheimer’s pathologic change, and individuals with evidence of abnormal tau and/or neurodegeneration but normal amyloid values are labelled as having non-AD pathologic change. The ATN classification can be applied independently of clinical staging, including cognitively normal individuals, such as those with SCD. About 20-25% of cognitively normal individuals, with or without SCD, have abnormal amyloid values, placing them in the Alzheimer’s continuum (11). The ATN classification serves as a common language among researchers and provides a structured method to characterize a sample, which has been beneficial for the research field. However, there are several challenges yet to overcome. The ATN framework has emerged as research framework and is not intended (yet) for clinical diagnosis and prognosis. It still needs to be thoroughly examined through longitudinal cohort studies and randomized controlled trials and altered if needed, in order to use in general clinical practice. Furthermore, the value of the ATN classification system in cognitively normal individuals with or without SCD still needs to be elucidated. Box 1. The SCIENCe project The SCIENCe project, which stands for Subjective Cognitive Impairment Cohort, is an ongoing cohort study in the Alzheimer Center Amsterdam. In this study, the contribution of different factors to SCD is evaluated and the longitudinal trajectory in relation to biomarkers is studied. The study started in 2014 and has included over 450 participants to date. Individuals are generally first referred to the Alzheimer Center by their general physician or medical specialist because of cognitive complaints, and receive an extensive work-up. When criteria for MCI or dementia are not met and there is no other neurological or psychiatric disease that could explain the cognitive complaints, individuals are labelled SCDand are subsequently invited to participate in the SCIENCe project (see Figure 2). Participants contribute to research by undergoing annual neuropsychological examinations, and optional blood tests, lumbar punctures and positron emission tomography (PET) scans. Yearly, the diagnosis of SCD is re-evaluated. If there are signs of cognitive deterioration, participants are offered a referral to clinical care. The majority of the research conducted in this thesis involves individuals with SCD from the SCIENCe project.