188 Chapter 8 The main focus of this thesis is on the value of abnormal biomarkers. Nevertheless, as shown in chapter 2, the majority of individuals with SCD have normal AD biomarkers and physicians might be unsure whether reassurance of these individuals is justified. Chapter 2 shows that these individuals have a very low rate of clinical progression to MCI or dementia during follow-up. None progressed to AD dementia, while only 2/175 individuals progressed to non-AD dementia. It is much more likely their subjective cognitive complaints have a non-neurodegenerative etiology (35, 36). Although chapters 3 and 7 suggest that grey zone amyloid burden could already be associated with memory decline and a higher rate of changing to amyloid positivity, future studies should investigate the long-term risks of clinical progression in this group of individuals since these are not known yet. Overall, the results presented in this thesis suggest that individuals with normal AD biomarkers could be reassured with the fact that the rate of clinical progression is very low. Grey zone amyloid burden could be a reason to offer follow-up. Physicians should be aware of other causes of subjective cognitive complaints such as normal aging, depressive feelings or sleeping disorders, and these should be addressed and if possible, treated. Concluding remarks AD is a complex disease, with a long predementia stage. This thesis shows biomarkers for amyloid, tau and neurodegeneration can be used to identify which cognitively normal individuals with SCD are at risk of clinical progression to MCI or dementia. The relationship between biomarkers and cognitive decline or clinical progression is robust, since different definitions of biomarkers produced similar results. In addition to AD biomarkers of amyloid, tau and neurodegeneration, cerebral blood flow plays a role in the early pathogenesis of AD since it is associated with amyloid accumulation and cognitive decline. Finally, biomarkers are not static but change over time, with a large variety in the order of biomarkers becoming abnormal, suggesting there are multiple pathways in the development of AD. This thesis contributed to early identification of AD pathology and highlights the central role of biomarkers in diagnosis and prognosis in individuals with SCD.
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