Imaging tau pathology using PET: Towards a better understanding of Alzheimer’s disease pathophysiology and clinical implementation

Alzheimer’s disease is the most common cause of dementia and contributes to approximately 60-70% of all dementia cases. The main pathological characteristics of Alzheimer's disease include the accumulation of amyloid-beta plaques and neurofibrillary tau tangles. Central in this thesis was the use of positron emission tomography (PET) imaging to quantify and visualize pathological processes associated with Alzheimer’s disease in the living human brain. The overarching aims of this thesis were to extend our knowledge on the pathophysiology of Alzheimer's disease using tau-PET imaging, and to investigate the clinical utility of tau-PET imaging. In a unique cohort of genetically identical twins, we found that twins of the same pair were comparable in tau load and tau spatial distribution indicating that genetic factors play a role in the accumulation and spreading patterns of tau. However, some twin-pairs showed large dissimilarities in tau, indicating that there is a role for environmental factors as well. Moreover, using genetically identical twin-pair difference analyses, we tested hypotheses of causality between amyloid-beta, tau, neurodegeneration and cognition, and found that these associations are minimally affected by (genetic) confounding, which is valuable information for clinical trial designs. We further investigated the role of tau in the pathophysiology of Alzheimer's disease by examining associations with vascular burden and synaptic loss. We found that the co-presence of cerebral microbleeds and amyloid-β pathology was associated with greater tau accumulation in cognitively unimpaired (but not impaired) individuals, and that the location of tau pathology in the brain spatially overlapped with the location of synaptic loss in the brain in patients with Alzheimer's disease dementia. Finally, we aimed to investigate the clinical utility of tau-PET, which is of importance in light of the recent FDA-approval of the first tau-PET radiotracer. We found that the FDA-approved tau-PET visual read method is reliable, stable and accurate for clinical implementation, and harbors prognostic value. We also found that while tau-PET and plasma pTau181 perform equally well in predicting the presence of amyloid-β pathology, tau-PET outperforms plasma pTau181 in predicting cognitive decline and disease stage. In conclusion, this thesis showed that PET measures of tau pathology can provide valuable insights into Alzheimer’s disease pathophysiology and can reliably be implemented in the clinic for a variety of purposes. Further steps need to be taken to further explore the prognostic potential of tau-PET.