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NIH grant 1K99AG097980-01A1: Lifespan Cellular and Spatial Mechanisms Linking Brain Aging and Alzheimer's Disease in the Human Prefrontal Cortex
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Hui Yang. Award: $133110.
Start: 2026-09-05T00:00:00.
PROJECT SUMMARY / ABSTRACT
The prefrontal cortex (PFC) supports executive function and cognition but undergoes profound cellular and
molecular remodeling from prenatal development through aging, changes that may influence vulnerability to
Alzheimer’s disease (AD). How age-aligned cellular transitions, intercellular communication, and spatial
organization collectively shape cognitive resilience or disease susceptibility remains unknown. This proposal
will integrate single-nucleus and spatial transcriptomics with machine-learning models for spatiotemporal
inference to establish a comprehensive lifespan reference of the healthy human PFC and identify AD-specific
deviations. In the mentored (K99) phase, I will harmonize single-nucleus RNA-seq data from the PsychAD
Consortium and public resources spanning the first trimester to over 100 years to reconstruct unified cross-
lineage pseudotime trajectories and pseudotime-aware intercellular communication networks, providing a
holistic view of cellular maturation and signaling dynamics across life stages. In parallel, I will integrate publicly
available 10x Visium datasets to define age-related spatial remodeling of cell types, gene-expression gradients,
and neighborhood interactions. In the independent (R00) phase, I will generate new high-resolution Xenium 5K
datasets spanning prenatal through aging stages to complete a lifespan-resolved spatial atlas and extend these
analyses to AD by mapping disease-related divergence from healthy trajectories and validating disrupted
cellular niches and signaling networks. This integrative framework will uncover cellular and spatial mechanisms
linking normal aging to AD pathology, advancing molecular understanding of cognitive resilience and
neurodegeneration. Under the mentorship of Drs. Panos Roussos, Guo-Cheng Yuan and Alison Goate, I will
receive interdisciplinary training in aging neuroscience, advanced computational approaches and
neurodegeneration. My independent laboratory will integrate multi-modal transcriptomic approaches to uncover
the cellular and molecular mechanisms underlying cognitive decline and AD vulnerability, identifying potential
therapeutic targets. In sum, this work will provide an integrated framework for understanding the molecular and
cellular basis of cognitive aging and neurodegeneration. More broadly, the additional training afforded by this
award will ideally prepare me to launch an independent research program dedicated to uncovering stage-
specific mechanisms of brain aging and developing targeted strategies to preserve cognitive function and
prevent neurodegenerative diseases.document fetched 2026-09-13 02:45