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NIH grant 1K99AG101485-01: Brainstem-cortical network biomarkers of cognitive resilience and decline in aging and preclinical Alzheimer's Disease
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Hengda He. Award: $132300.
Start: 2026-09-11T00:00:00.
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.document fetched 2026-09-20 02:42