Synaptic loss is a major feature of symptomatic AD. Conversely, abundance of synapses may confer resilience to cognitive decline in the presence of AD pathology. The pathology-defining features of AD are amyloid plaques and neurofibrillary tangles and their presence and distribution can be spatially estimated in-vivo with amyloid and tau PET. Although these biomarkers can inform on the degree and location of pathology, they do not provide an indicator of their effect on collocated or extended in-network neural damage including synaptic density.~SV2A is expressed ubiquitously in synapses and the capability of assessing SV2A in vivo may provide a direct indicator of synaptic health. Such information would be of high importance for staging the level of synaptic loss or conversely synaptic abundance in the AD continuum and may potentially improve prognostic precision. The PET radioligand [C-11]UCB-J is a marker of SV2A.~The overarching goal of this project is to use [C-11]UCB-J to obtain spatial information on neuronal synapse abundance and inform upon disease progression. The investigators propose to collect longitudinal amyloid, tau, and SV2A PET in participants in the Wisconsin ADRC and WRAP across the clinical stages of AD, including cognitively unimpaired biomarker negative, unimpaired biomarker positive, MCI, and dementia due to AD.~Specific Aim 1). Determine the extent to which [C-11]UCB-J provides unique information from MRI regarding neurodegeneration. Approach: The investigators will recruit N=60 cognitively unimpaired participants, N=30 MCI participants, and N=30 participants with AD dementia to undergo PET imaging with [C-11]UCB-J. MRI will include anatomic and diffusion connectivity MRI. When available, ancillary cerebrospinal fluid (CSF) indicators of neurodegeneration and synapse function will be examined for relationships with UCB-J.~Specific Aim 2). Determine the rate of synapse loss as reflected by [C-11]UCB-J signal across all participants. Rationale: Trajectories of synaptic loss are unknown in vivo. Approach: The investigators will determine the longitudinal trajectories of regional synapse loss that are observed over time among participants who undergo repeat [C-11]UCB-J (separated by two years, same participants scanned for Aim 1). The investigators will also examine trajectories by amyloid and tau load. Quantifying longitudinal synaptic loss is expected to eventually facilitate the identification of individuals who are progressing to dementia, as well as inform upon changes that are normal for age.~Specific Aim 3). Determine the extent to which [C-11]UCB-J associates with cognitive decline. Rationale: The investigators expect that lower baseline SV2A density and longitudinal decline in SV2A density in the medial temporal lobe will be associated with faster progression of cognitive decline. The investigators will also test the extent to which harboring multiple pathologies (↑amyloid, ↑tau, and ↓SV2A density) contributes to cognitive decline. Approach: The investigators will examine core indices of cognitive status and continuous measures of cognitive function from the source cohorts and utilize mixed effects models to ascertain the effect of UCB-J amyloid and tau on cognition.~Specific Aim 4). Determine factors which impact synapse loss. Rationale: Several risk factors for cognitive decline and dementia have been identified including potentially modifiable factors such as insulin resistance and vascular risk factors. Approach: The investigators will determine cross-sectional and longitudinal trajectories of regional synapse loss in relation to risk factors for cognitive decline and dementia. In order to determine insulin resistance, the investigators will perform blood draw and assess fasting glucose and insulin values to determine the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). The impact of potentially modifiable risk factors on synapse loss in vivo is currently unknown. This aim will address this gap in knowledge, results which may translate to strategies for reducing dementia risk.
The overarching goal of this project is to use [C-11]UCB-J to obtain spatial information on neuronal synapse abundance and inform Alzheimer's disease (AD) progression. The investigators propose to collect longitudinal amyloid, tau, and Synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) in participants in the Wisconsin Alzheimer's Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer's Prevention (WRAP) across the clinical stages of AD, including cognitively unimpaired biomarker negative, unimpaired biomarker positive, mild cognitive impairment (MCI), and dementia due to AD.