Project Summary/Abstract Alzheimer's disease (AD) is a global issue that must be solved urgently because of its significant impact on public health and economics, as well as the quality of life of individuals in the United States and other aging societies. Once cognitive impairment occurs in the AD continuum, there are great difficulties in modifying the devastating disease process. Pathological changes inside the brain begin silently many years before the onset of cognitive impairment. This long “preclinical” stage provides us with an opportunity for timely therapeutic and preventive interventions. Therefore, the development of tools that can predict future cognitive decline during the preclinical stage of AD is crucial. There is a consensus that neurodegeneration has a stronger correlation with cognition in the disease progression along the AD continuum, compared to the diagnostic AD biomarkers such as amyloid and tau proteins. In contrast, neuroimaging modalities currently used to detect biomarkers for neurodegeneration are not sensitive enough to detect minute changes during the preclinical stage of AD. Here, Dr. Yuto Uchida hypothesized that myeloarchitectonic features observed in the entorhinal-hippocampus pathway could serve as sensitive neurodegenerative biomarkers given that AD pathogenesis occurs in the entorhinal cortices. In this project, he will conduct a proof-of-concept study to examine microstructural neurodegeneration of the entorhinal- hippocampus pathway in a combined framework: ex vivo ultra-high-field quantitative MRI followed by histological verification in Aim 1, and in vivo ultra-high-field quantitative MRI in clinical settings for healthy controls in Aim 2 and for preclinical and prodromal AD individuals in Aim 3. In Aim 1, postmortem hemibrains will be scanned on a human 7T MRI scanner and compared with the corresponding histology in the entorhinal-hippocampus pathway to fill the gap between the MRI findings and microscopic observations. In Aim 2 and Aim 3, cutting-edge, deep learning-based susceptibility tensor imaging (DeepSTI) and DeepSTI-based tractography will be applied to an ongoing cohort study (RF1AG071515), which comprises healthy, preclinical, and prodromal AD individuals. In Aim 2, reference ranges for quantitative MRI measures in the entorhinal layer II and the perforant path fibers will be established. In Aim 3, comparative analyses of these quantitative MRI measures among the groups will be done cross-sectionally, which will be followed by a longitudinal study to examine these associations with cognitive decline along the AD continuum. In summary, the long-term objective of this K99/R00 application is to support Dr. Yuto Uchida’s ability to conduct studies aimed at developing biomarkers for neurodegeneration that can visualize and quantify microstructural brain alterations during the preclinical stage of AD using ultra-high- field quantitative MRI. Dr. Uchida will be co-mentored by Drs. Kenichi Oishi, Xu L...