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Molecular signatures of cognitive resilience against aging and Alzheimer's disease at single-cell resolution

Award Number: F99AG095117
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Molecular signatures of cognitive resilience against aging and Alzheimer's disease at single-cell resolution - PROJECT SUMMARY/ABSTRACT Cognitive decline is a hallmark of aging and Alzheimer’s disease, which increases disability and deteriorates life quality. Some ancestries are disproportionately affected, likely due to genetic susceptibility and environmental, vascular, and metabolic risk factors. Despite this burden, neither age nor Alzheimer’s fully explain the wide variation in cognitive trajectories, indicating that other factors contribute to cognitive decline. These factors can be elucidated by studying “resilient” individuals, defined as those who maintain cognition despite aging or severe Alzheimer’s pathology. Studying resilience can help identify therapeutic targets to preserve cognition in individuals at risk. Yet the therapeutic potential of resilience remains limited by gaps in our understanding of its molecular basis. Recent studies, including those from our lab, link resilience to autophagy, immunomodulation, and transcriptional changes in astrocytes and neurons, with a single study exploring the epigenetic landscape of resilience to Alzheimer’s. However, much remains to be understood about how these insights assemble into cell-type-specific regulatory programs of resilience across brain regions and higher-risk populations, how these signatures vary in proximity to pathology and neighboring cells and whether pharmacological interventions can bolster resilience. In this proposal, I will address these knowledge gaps by characterizing cell-type-specific cellular, transcriptional and epigenetic signatures of resilience during my predoctoral work using single-nucleus RNA+ATAC-seq on a cohort from Rush University spanning three brain regions and uniquely enriched for resilient donors from ancestries with elevated Alzheimer’s disease burden, including those resilient to advanced age with low Alzheimer’s pathology (age-related resilience) and those resilient to severe Alzheimer’s pathology (Alzheimer’s-related resilience). During my postdoctoral phase, I will map these resilience signatures to their spatial context using cutting-edge spatial transcriptomics, revealing how the neuropathological microenvironment and neighboring cells influence resilience. Finally, I aim to translate these molecular insights into actionable therapeutic strategies by screening FDA-approved compounds to shift the transcriptome from susceptibility to resilience in human-induced pluripotent stem cells derived from donors with advanced age and severe Alzheimer’s pathology. This investigation will prioritize therapeutic targets and potential compounds for preserving cognition across representative populations. These goals align with NIA's mission to extend healthspan by deepening our understanding and treatment approaches of age-related conditions. Guidance from an interdisciplinary mentoring team will ensure the success of the proposed research as I transition through the predoctoral and postdoctoral phases of this award. Training in advanced statistical modeling, single-cell and spatial omics, and drug screening will equip me to achieve my long-term goal of becoming a well-rounded, independent investigator who leverages resilience to improve cognitive health in aging and neurodegenerative diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $51,614 )
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	1	6/23/2026	NEW	$0
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	1	6/23/2026	NEW	$51,614
														Subtotal = $51,614

Grand Total All Awards = $51,614

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Molecular signatures of cognitive resilience against aging and Alzheimer's disease at single-cell resolution

Award Number: F99AG095117

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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