Tracking the course of preclinical Alzheimer’s disease Within a genetically Identical and cognitively Normal older twin Sample: T.W.I.N.S.

The general aim of this thesis was to investigate early pathophysiology of Alzheimer’s disease (AD) in cognitively unimpaired older individuals (including monozygotic twin-pairs) and investigate the associations of amyloid-β and tau biomarkers (as measured with PET and CSF), APOE genotype and AD-PRS with cognitive decline. We further studied the relative contribution of genetic and environmental influences to AD biomarkers, cognitive decline and to the relation between these markers using a monozygotic twin design. The key findings of this thesis are listed below: - Monozygotic twin-pair correlations show that environmental factors substantially influence the onset of amyloid-β production and aggregation markers, tau markers and cognition. - Increased amyloid-β production, as assessed by CSF BACE-1, is a very early feature of AD pathophysiology. - Cognitively unimpaired older individuals who have abnormal CSF amyloid-β and tau markers show steeper decline in memory and language functioning and these associations are in part determined by the same underlying genetic factors. - A high AD-PRS and APOE genotype are associated with amyloid-β positivity and cognitive decline over time. - The association of APOE genotype on cognitive decline was dependent on amyloid-β positivity, whereas a high AD-PRS explained variance in cognitive decline independently of APOE genotype and amyloid-β positivity. - Discordant amyloid-β negative twins show higher conversion risk to an amyloid-β positive status over time compared to concordant amyloid-β negative twins. - Twin-pairs who are further along the AD continuum, based on the longitudinal amyloid-β PET twin concordance model, were generally older, more often APOE ε4 allele carriers, showed highest levels of tau and steepest decline in memory performance. - Associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. - In line with the amyloid cascade hypothesis, effects of amyloid-β on neurodegeneration and cognitive decline are fully mediated by tau. This thesis shows that besides biomarkers for amyloid-β and tau, also genetic determinants of AD can be used to identify cognitively unimpaired individuals at risk of cognitive decline. The very first cognitive changes in AD are found in the memory and language domains. The relationship between biomarkers and cognitive decline is robust, since different modalities of biomarkers produced similar results. Finally, the onset and development of AD underlies a complex interplay of genetic and environmental influences, where environmental factors seem to influence the onset of amyloid-β aggregation. This thesis contributed to early identification of AD pathology and highlights the important role of biomarkers for diagnosis in cognitively unimpaired populations.