Neuroimaging and genetics of the glymphatic system in Alzheimer's disease - PROJECT SUMMARY/ABSTRACT Alzheimer's disease, a relentless neurodegenerative illness spanning one to two decades, not only devastates the individuals affected by it but also takes a toll on their loved ones. As the most prevalent neurodegenerative disease, it poses a staggering cost to our society. Addressing the gradual progression of Alzheimer's disease demands a sustained, long-term intervention. To truly understand the dynamic and progressive characteristics of the disease over time, we must first delve into the upstream mechanisms that may falter as we age, leading to the accumulation of toxic proteins. At the forefront of these mechanisms is the brain’s waste clearance system, also known as the glymphatic system. While animal models have shown the glymphatic system`s ability to clear out protein waste, human imaging and genomic markers of this system remain understudied and are thus crucially needed. Unveiling the intricacies of brain waste clearance has the potential to revolutionize diagnostic and therapeutic approaches in neurodegenerative diseases and aging, enabling interventions before the onset of neurodegeneration. Our research proposal aims to test novel, non-invasive markers for characterizing the glymphatic system through a combination of neuroimaging and genomics. Employing three complementary imaging measures — intravoxel incoherent motion (IVIM), 3D amplified MRI, and perivascular space volume—, we will gain a comprehensive understanding of the glymphatic system. These methods, acquired at the Stanford Alzheimer’s Disease Research Center (ADRC) during simultaneous PET-MR imaging, will help us identify associations between IVIM flow, bulk brain motion, and the accumulation of Aβ and tau proteins. In addition, we will leverage a substantial dataset from the Alzheimer's Disease Sequencing Project (ADSP) to explore the relationship between Alzheimer's disease genomics and perivascular space volume, as well as perivascular space genomics and Alzheimer's disease risk. Our proposal encompasses two specific aims: 1. Examine correlations of glymphatic clearance imaging with tau PET and memory in both Alzheimer's disease and control groups in the Stanford ADRC. 2. Investigate the relationship between genomics and biomarkers of glymphatic clearance in connection with Alzheimer's disease in the ADSP cohorts. In summary, our research aims to fill the gap in understanding the role of the human glymphatic system in the context of Alzheimer's patients and healthy aging control by investigating relationships between protein accumulation, genomics, and cognitive status.
