183 Summary and general discussion clinical progression, but only HV, NfL and GFAP added predictive value beyond abeta and p-tau. These results indicate different N biomarkers reflect different aspects of neurodegeneration and should not be used interchangeably. Our results do not allow to choose one most suitable biomarker for N, yet they do illustrate the added prognostic value of N beyond A and T. In chapter 5, we investigated the relationships between genetic determinants of AD, ATN biomarkers and risk of dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. APOE was not included in the PRS and was analyzed separately. We used amyloid PET or CSF abeta to define A, CSF p-tau to define T, and MTA on MRI to define N. The PRS and APOE ε4 carriership were associated with amyloid positive ATN profiles, and APOE ε4 additionally with isolated increased tau (A-T+N-). A high PRS and APOE ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers. These results imply genetic variants beyond APOE are clinically relevant and contribute to the pathophysiology of AD. In chapter 6, we investigated the associations between relative cerebral blood flow (rCBF), amyloid burden and cognition. Individuals underwent dynamic [18F]florbetapir PET, enabling the calculation of mean binding potential (BPND) and R1 (proxy for relative (r)CBF). Eighty-three individuals underwent a second dynamic [18F]florbetapir PET. Both amyloid burden and rCBF independently contribute to cognitive decline over time. Furthermore, despite absence of cross-sectional associations, high baseline amyloid burden was associated with a subsequent decrease in rCBF, while inversely low baseline rCBF was associated with subsequent increase in amyloid burden. These results suggest that amyloid accumulation and decrease in rCBF are two disease processes, which both provide unique predictive information for cognitive decline and enhance each other longitudinally. In chapter 7, we studied longitudinal change in ATN biomarkers, and investigated which factors were associated with change in A status specifically, in a group of 92 individuals with SCD. We used [18F]florbetapir PET for ‘A’, [18F]flortaucipir PET for ‘T’ and medial temporal atrophy score on MRI for ‘N’. Thirty-nine individuals had complete biomarker data at baseline and follow-up, enabling the construction of ATN profiles at two time points. Seventeen individuals (44%) changed to a different ATN profile over time. Only 6/17 followed the hypothetical sequence of A → T → N, while 11/17 followed a different order, showing the large variability in the order of ATN biomarkers becoming abnormal. APOE ε4 carriership inferred an increased risk of changing from A- to A+. Individuals who became A+ at follow-up showed subtle decline on tests for attention and executive functioning, confirming clinical relevance of amyloid positivity. 8
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