Longitudinal imaging of tau pathology across the AD spectrum using [18F]AV1451 PET

Dementia is the number one cause of death in The Netherlands. Due to the ageing population, the number if people with dementia will rise to over 500.000 in 2040. As a result, it is now the most costly disease in the Netherlands. The healthcare costs of dementia are 5 billion Euro per year, and these costs are expected to rise with 2,5% every year. Currently no treatment exist to cure or even slow down dementia. New methods to detect and treat dementia are therefore urgently needed. The leading cause of dementia is Alzheimer’s disease (AD). The prevailing theory to explain the cause of AD has been the amyloid hypothesis. This hypothesis postulates that amyloid-beta deposits are the initiator of a cascade of downstream events. However, therapeutic drugs targeting these amyloid plaques have thus far not been effective in delaying the disease course. In addition, it has been observed that amyloid plaque deposition does not correlate very well with neuronal loss and with cognition. As such, amyloid biomarkers are not very helpful in the prognosis of patients with AD. The second core neuropathological hallmark of AD is tau. Tau is an intracellular protein, which under normal conditions has an important role in the stabilization of microtubules. In AD, tau becomes hyperphosphorylated resulting in intracellular deposits of neurofibrillary tangles (NFT). Post-mortem studies show that NFT in AD spreads across the brain in a very specific pattern that closely correlates with symptoms, disease severity and disease progression. However, in-vivo assessment of NFT patterns was until very recently impossible since no selective positron emission tomography (PET) tracer for tau existed. The newly developed tracer 18F-AV-1451 selectively binds to the tau isoforms associated with AD and allows for imaging tau pathology with PET. The goal of this project is to longitudinally investigate tau patterns in vivo in patients using PET, and relate these patterns to changes in cognitive function and brain atrophy. This allows for detection of AD progression, directly related to the rate of neurodegeneration. The VUmc is the only center in the Netherlands with experience concerning 18F-AV-1451 imaging, and has a strong track record for exact quantification of PET using dynamic PET scans. This project investigates changes in tau patterns over time using 18F-AV-1451 dynamic PET scans in patients with subjective cognitive decline (SCD), Mild Cognitive Impairment (MCI) and AD dementia. First, these changes are determined across the clinical spectrum in AD. Subsequently, it is determined whether these changes are: i) associated with longitudinal decline in neuropsychological functions, ii) better predictors of cognitive decline than established prognostic markers; iii) associated with rates and patterns of brain atrophy; and iv) associated with changes of phosphorylated-tau and total-tau in cerebrospinal fluid. Lastly, the variation in meaning and value of prognosis are investigated, i) during the course of the disease, and ii) between patients and informal caregivers. This part is aimed at assessing how (potential) patients and informal caregivers perceive the value of tau PET as a prognostic tool. The project has a strong link with patients and caregivers as well as private parties that develop novel imaging tracers. It furthermore connects with several themes of the JPND research strategy, more specifically ‘disease definitions and diagnosis’ and ‘developing therapies, preventive strategies and interventions’. In summary, we aim to characterize the tau PET biomarker 18F-AV-1451 as a prognostic marker in different stages of AD. Applicability in clinical and research settings will be enhanced by development of reliable analytical models and interpretation of the data is fed by the Memorabel I work packages ‘18F-AV-1451 binding to post-mortem tissue and tracer kinetic modeling’. Frequent interactions with patients and caregivers will ensure that the setup and outcomes of this study meet the needs of all involved parties. This project leads to a validated measure to accurately assess AD status and progression. Additionally, it enables testing efficacy of treatments aimed at tau. This will ultimately result in novel and improved ways to treat AD patients.