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Utilizing gene-level biomarkers of AD to identify pathophysiological mechanisms in human neurons

Award Number: R21AG083638
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Utilizing gene-level biomarkers of AD to identify pathophysiological mechanisms in human neurons - Abstract Summary Recent advances AD therapeutics increases the urgency to identify individuals at risk for developing Alzheimer’s disease (AD). This effort can likely be accelerated using stem cell biology approaches which have led to the ability to generate human induced neurons (HiN) directly from easily obtainable patient cells such as fibroblasts. This serves as a powerful tool for studying aging and disease-related processes in clinically relevant cell types. Meta-analysis studies of existing transcriptomic databanks from AD patients and healthy individuals without dementia (nonAD) have also provided new insight into underlying pathophysiological drivers contributing to a diagnosis of AD. While these gene expression profiles have been identified for AD risk which carryover from the individual to their directly transformed neurons (human induced neuron, HiN). This is a crucial missing link needed to capture the physiological outcomes of these gene network profiles in order to identify associated mechanisms of metabolic stress, pathological protein aggregation and synaptic pathophysiology – all key features of AD. Therefore, we will apply neurophysiological and cellular functional analyses to HiNs derived from representative individuals diagnosed with sporadic or familial AD, as well as age/sex-matched nonAD controls, to identify functional consequences of these genomic variations in the human population. Our overall objective is to identify gene-pathway based biomarkers or risk factors for AD and define the neuronal pathophysiological phenotypes associated with these gene pathways. We will test the hypothesis that synaptic signaling, metabolism and protein handling processes in neurons derived from the AD population will reflect the alterations in gene pathways that distinguish healthy aging processes from AD pathogenesis, and thus can serve as important biomarkers. In Aim 1 we will identify mitochondrial functional deficits associated with alterations in glucose metabolism gene pathways in AD. In Aim 2 we will identify pathological manifestations of altered gene pathways regulating autophagy and protein mishandling in AD patients. In Aim 3 we will identify neurophysiological and synaptic signaling effects corresponding with altered gene networks in AD that underlie cognitive decline. The combination of our expertise in induced neuron production as well as bioinformatics and neurophysiology assays makes this a powerful and innovative proposal that will provide important insights into risk factors and biomarkers of AD. This comes at a crucial time in the AD field where it is imperative to identify at risk individuals early in order to maximize benefits of new therapeutics becoming available.


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: 2025 ( Subtotal = $0 )
2025	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Aging Research	000	1	12/18/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $422,645 )
2023	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Aging Research	000	1	8/14/2023	NEW	$422,645
														Subtotal = $422,645

Grand Total All Awards = $422,645

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Utilizing gene-level biomarkers of AD to identify pathophysiological mechanisms in human neurons

Award Number: R21AG083638

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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