Tracking the Effects of Amyloid and Tau Pathology on Brain Systems and Cognition in Early Alzheimer’s Disease

ended

Alzheimer’s disease (AD) is a tremendous burden and there are still no therapies available. Most clinical trials have focused on the late disease stages where neuronal damage is already severe and irreversible. To intervene in earlier stages, it is essential to understand how AD pathology affects brain systems early in the disease. Beyond that, we need better markers to identify individuals at an early asymptomatic stage that will likely deteriorate in the coming years as well as measures of treatment response to assess the benefit of a treatment. I focus on two functional brain systems that are critical for memory in humans and are very early affected by AD pathology. With the powerful and novel combination of positron-emission-tomography and ultrahigh-field magnetic resonance imaging, I will unravel the early effects of AD pathology on brain connectivity and activity, grey matter loss and memory function within both brain systems. I will use a pseudo-longitudinal design to study changes in brain system integrity and memory during disease progression in the very early stages of AD. To identify predictive markers of progression, I will use monthly repeated smartphone-based assessments throughout one year to i) define cognitive trajectories of individual memory decline, ii) characterize stage-specific decline rates, and ii) determine the best cognitive and imaging markers for prediction of cognitive decline. Taken together, this proposal will result in a more profound understanding of the earliest stages of AD and provide novel markers that will improve patient selection as well as assessment of treatment response in future clinical AD trials. This will advance the development of new disease-modifying therapies and early clinical diagnosis. Importantly, realizing this proposal will provide critical training of scientific and transferable skills that are required to follow my research interests and to set up my own research group in the future.