Brainstem-cortical network biomarkers of cognitive resilience and decline in aging and preclinical Alzheimer's Disease
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PROJECT SUMMARY The prevalence of Alzheimer's disease (AD) and related dementias is projected to affect 78 million individuals worldwide by 2030. To facilitate timely interventions and disease prevention, early detection and personalized risk assessment strategies are critical. Current AD pathology metrics often overlook the brain's network organizations, particularly the roles of subcortical and brainstem systems. The goal of this K99/R00 proposal is to elucidate how AD pathology interacts with brain networks, with a specific focus on subcortical and brainstem networks, to better understand their integrative roles in cognitive reserve/resilience and cognitive decline during aging and preclinical AD stage. During the mentored K99 phase, Aim 1 will establish and validate a novel connectome-informed network-based amyloid-beta (Aβ) metric designed to enhance the early detection and prediction of cognitive decline. Aim 2 will evaluate how Aβ pathology affects connectivity within critical cortical networks, assessed through functional magnetic resonance imaging (fMRI) during a working memory task. To achieve these goals, the PI will receive structured training and mentorship in: (1) cognitive aging and AD pathology, (2) brainstem neuroanatomy and behavioral neuroscience, (3) advanced statistical modeling, and (4) professional development for transition into independence. The training will prepare the PI to independently execute the proposed research focused on brainstem networks in the R00 phase. Aim 3 will develop and validate a robust fMRI analysis pipeline for functional network extraction within the brainstem. Then, brainstem network connectivity will be investigated in relation to Aβ pathology and cognitive performance. Aim 4 will examine the involvement of brainstem networks in supporting cognitive reserve and resilience. My central hypothesis is that brainstem systems support compensatory reorganization of large-scale cortical networks in response to Aβ pathology. By integrating individualized brain network connectivity, this project will develop sensitive biomarkers for the early detection of AD-related cognitive decline in older adults during the preclinical AD stage. These advances are directly aligned with the National Institute on Aging’s mission to extend healthy, active years of life through research on aging and age-related diseases. This proposal leverages multimodal neuroimaging techniques and advanced statistical modeling to elucidate the role of brainstem-cortical interactions in cognitive reserve/resilience and decline. These results will facilitate the development of novel, reproducible network-based biomarkers of AD pathology. The PI’s long-term goal is to support cognitive health in older adults by developing innovative network-based neuroimaging AD biomarkers, and personalized neuromodulation interventions targeting cognitive reserve and resilience mechanisms. The proposed training and research activities will support the PI to establish an independent research program at the intersection of multimodal neuroimaging, cognitive aging, and Alzheimer’s disease research.
