A multimodal examination of Alzheimer's disease pathology and synaptic loss

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia affecting nearly 7 million Americans, and the number of affected individuals is projected to rise as the nation ages. In addition to the defining features of amyloid and tau pathology, synaptic loss associates with cognitive dysfunction in AD, with postmortem investigations revealing substantial reductions in synaptic density among people with dementia, and studies suggesting this process may be linked with tau pathology. However, the accrual of AD pathology and associated synaptic loss has been difficult to measure in living humans across the AD clinical and biological continuum. Thus, this F31 proposal aims to address this gap using in vivo measures of tau pathology secretion and neuroimaging of synaptic density to better understand the biologic and clinical progression of AD. My proposed aims are to 1) determine the extent to which tau pathology secretion associates with synaptic loss among richly characterized participants on the AD continuum using blood biomarkers of AD and synaptic positron emission tomography (PET), and 2) determine the regional relationship between tangle pathology and synaptic density using tau PET and synaptic PET. This project will leverage the resources of the NIA-funded Wisconsin Alzheimer’s Disease Research Center. The sample will include cognitively unimpaired AD biomarker negative and positive participants, as well as individuals with mild cognitive impairment and participants with dementia due to AD. The project leverages sophisticated and promising measures, including a novel plasma biomarker of brain-derived tau pathology, hyperphosphorylated tau at amino acid residue 217 (pTau217) and [C-11]UCB-J, a PET radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). This synaptic vesicle protein is found in presynaptic nerve terminals throughout the brain and is a promising target for studying synaptic loss in individuals across the AD continuum. The proposed study is expected to address gaps in knowledge about the progression of AD and the factors that contribute to cognitive decline, and inform future intervention studies to mitigate cognitive decline in AD. Finally, my mentorship team and I have developed a comprehensive and integrated training plan for this fellowship which will support my research training as a committed predoctoral student from a community which is underrepresented in the biomedical research workforce.