107 Risk of dementia related to APOE ε4 and a polygenic risk score BACKGROUND Neuropathologically, Alzheimer’s disease (AD) is defined by the presence of amyloidbeta plaques and neurofibrillary tau tangles (1). In vivo, a research framework for AD proposed that individuals can be categorized based on biomarker evidence of pathology. According to the ATN system, each individual is rated for the presence of amyloid-beta (A), hyperphosphorylated tau (T), and neurodegeneration (N), resulting in eight possible biomarker combinations (2). This categorization is independent of the cognitive stage of the individual, and therefore, cognitively normal individuals can be identified who already harbor the first pathophysiological changes associated with AD, which is referred to as preclinical AD or stage 2 AD (3). It is important to identify which cognitively normal individuals, with or without subjective cognitive decline (SCD), are at risk of future cognitive deterioration. Research interest of secondary prevention trials is shifting increasingly to these early stages, because these individuals could potentially benefit most from disease modifying therapy. The ATN-biomarkers - particularly biomarkers for amyloid pathology - predict cognitive decline and clinical progression (4-6). Genetics have also potential for risk estimation of clinical progression. The Apolipoprotein E (APOE) ɛ4 allele is a strong genetic risk factor for AD, and it has been consistently linked to a higher amyloid burden (7). Besides APOE, many other genetic variants have been identified during recent years that are also associated with AD (8-10). Each of these genetic variants has a small individual effect, but combined in a polygenic risk score (PRS) they are able to differentiate individuals with AD dementia from healthy controls in population-based studies (11-13). The extent to which a PRS is associated with biomarkers is less clear, as former studies provided contradictory results (14-19). Our aim was to investigate the relationship between genetic risk factors for AD and the ATN-classification in cognitively normal individuals presenting with worries about their memory at a memory clinic. Furthermore, we aimed to explore the relationship between genetic risk factors and clinical progression to dementia. 5