The use of biomarkers in non-demented AD patients for clinical trial design and clinical practice

The aim of the thesis was to investigate the use of biomarkers for trial design in non-demented subjects with AD. In addition, we investigated the perceived usefulness of biomarkers in clinical practice. In chapter 2 .1 we found that biomarkers and cognitive markers showed a temporal order of change and that the markers showed different rates of decline in subjects with AD-asymptomatic, AD-MCI and AD-dementia. CSF Aß1-42 reached the maximum abnormality level in the asymptomatic stage and CSF tau in the MCI stage. The imaging and cognitive markers started to change in the asymptomatic stage and became abnormal in the MCI stage. The rate of change in these markers increased with increasing disease severity. The pattern of decline was distinct from that of subject without amyloid pathology, which showed a more benign pattern of change. Our results are, with some exceptions, in accordance to the hypothetical model of dynamic changes and may be helpful to determine stage specific outcome measures for clinical trials. In chapter 2.2 we studied the association of CSF Aβ 1-42 in non-demented subjects with SCD or MCI. We found that lower CSF Aβ 1-42 levels within the normal range are predictive for faster clinical progression in non-demented memory clinic subjects. This effect was more evident in subjects with MCI. For both SCD and MCI subjects, the predictive value of CSF Aβ 1-42 levels was stronger than CSF tau or p-tau levels. These results suggest that low normal CSF Aβ 1-42 levels could reflect the earliest changes in the brain that are relevant for AD. In chapter 2.3 we defined a cutoff for CSF aß1-42 with the use of data driven Gaussian mixture modelling. With Gaussian mixture modelling one assumes that the data are a mix sampled from two different distributions, which represent a normal and an abnormal population. With this method we determined a cutoff for abnormal CSF aß1-42 levels at 680 pg/ml. This cutoff was independent of the cognitive stage and APOE genotype. The cutoff was higher in older than in younger ...