157 Longitudinal change in biomarkers INTRODUCTION The most common cause of dementia is Alzheimer’s disease (AD), which is characterized by the accumulation of amyloid beta plaques and neurofibrillary tau tangles (1). The ATN classification provides a framework to diagnose AD based on biomarkers providing an indication of these pathologic changes (2). In this framework, individuals are classified by the presence or absence of amyloid (A), hyperphosphorylated tau (T) and neurodegeneration (N), resulting in eight possible ATN profiles. We previously showed that in cognitively normal individuals with subjective cognitive decline (SCD), A+ was associated with a higher risk of dementia (3). According to the amyloid cascade hypothesis, the accumulation of amyloid in the brain initiates a series of events including the formation of neurofibrillary tau tangles and neuronal cell loss, eventually resulting in cognitive decline (4). Therefore, it is assumed that individuals become A+ before turning T+ or N+. Only a few studies evaluated the temporal ordering of ATN biomarker abnormality in a longitudinal manner. One study in a mixed population of cognitively normal individuals and individuals with mild cognitive impairment (MCI) indeed found that most often, A became abnormal first, yet also described there were multiple routes, specifically A → T → N, A → N → T, T → A → N and N → A → T (5). In the ATN classification, biomarkers are treated as dichotomous variables. With research interest shifting to the very early stages of AD, ‘grey zone’ amyloid burden and subthreshold amyloid accumulation were found to be associated with memory decline, showing additional value of amyloid burden in the perithreshold range (6-8). One study in a population consisting of cognitively normal and MCI individuals investigated change from A- to A+ rather than accumulation rate, and found that lower baseline cognition and APOE ε4 carriership were predictive of changing to A+ (9). Investigating determinants of amyloid accumulation, specifically in the early stages of disease, would lead to a better understanding of the pathophysiology of AD and could help anti-amyloid trials target individuals at risk even earlier in the disease process (early secondary prevention). The aims of this study were to (1) identify determinants of change in amyloid status, (2) describe changes in ATN profiles over time and (3) evaluate change in amyloid status as predictor of cognitive decline, in cognitively normal individuals. 7