181 Summary and general discussion Key findings 1. More than half of individuals with SCD have normal biomarkers for amyloid, tau and neurodegeneration. 2. As a group, individuals with amyloid positive ATN profiles have an increased risk of clinical progression to dementia and a steeper decline in cognition. 3. Not only high amyloid burden, but also grey zone amyloid burden is associated with suboptimal memory function. 4. There is a high degree of heterogeneity in biomarkers that capture neurodegeneration, and correlations between different biomarkers are low. 5. A high AD-specific polygenic risk score is associated with amyloid positivity. 6. A high polygenic risk score and APOE ɛ4 carriership are associated with a higher risk of AD dementia, and when combined, a low PRS attenuates the detrimental effect of APOE ε4. 7. APOE ε4 carriership is associated with a higher amyloid accumulation rate and a higher risk of change to an amyloid positive status. 8. Amyloid accumulation and a decrease in relative cerebral blood flow are two AD disease processes which enhance each other longitudinally. Although associated, both provide unique predictive information for cognitive decline. 9. There is variability in the order of ATN biomarkers becoming abnormal. 8