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Investigating a molecular basis for Alzheimer's disease subtypes using multiomic data integration and machine-learning

Award Number: F31AG069441
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Investigating a molecular basis for Alzheimer's disease subtypes using multiomic data integration and machine-learning - PROJECT ABSTRACT Investigating a molecular basis for AD subtypes using multiomic data integration and machine-learning Despite intense investigation into preclinical Alzheimer’s Disease (AD) disease models, all potential disease- modifying drugs have failed in clinical trials. Numerous genetic studies have proposed a number of biological mechanisms, however there has been no consensus on the genetic etiology of AD. This is likely because the prevailing view of AD as a singular disease is oversimplified and does not consider heterogeneous pathogenic variation in AD genetic architecture. High-throughput studies indicate that AD is a result of complex, nonlinear interactions within and between the genome, transcriptome, epigenome, and proteome. While genome-wide association studies have successfully revealed genes associated with AD, these genes explain disease in a small proportion of the patient population, and the question of “missing heritability” remains. Thus, in Aim 1, I propose using linear and nonlinear methods in an integrated multiomics framework with machine learning to identify pathways significant in AD. While almost all AD patients present the hallmark b-amyloid and neurofibrillary tangle pathology, they also present significant variability in cognitive symptoms, behaviors, and neurophysiology. Given this, I hypothesize that inter-individual variation in AD-associated and immune pathways drives different disease etiologies across the patient population culminating in a common pathophysiology. One source of heterogeneity may be in immune pathways differentially regulating neuroinflammatory response during AD. In Aim 2, I propose using an unsupervised classification approach to determine subtypes of AD based on patient similarity in pathway variation across omic levels, imaging data, and phenotypic data. Specifically, I hypothesize that pathogenic variation within innate immunity pathways plays a critical role in driving different disease etiologies between patients. In aim 3, I propose characterizing each omic subtype by generating protein interaction networks for drug target prioritization. Knowledge from these aims will inform a shift in the current AD drug development paradigm by informing a precision medicine approach to target specific omic subtypes of AD instead of a “one size fits all” approach that has failed to date. Investigating genomic heterogeneity in AD through these aims has the potential to impact detection of pre-symptomatic AD individuals as well as reveal more insights into the complex genetic architecture of AD.


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: 2024 ( Subtotal = -$23,798 )
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	3	10/24/2023	NON-COMPETING CONTINUATION	$0
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	002	3	3/22/2024	NON-COMPETING CONTINUATION	-$7,964
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	3	2/23/2024	NON-COMPETING CONTINUATION	-$15,834
														Subtotal = -$23,798

Issue Date FY: 2023 ( Subtotal = $35,141 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	3	12/13/2022	NON-COMPETING CONTINUATION	$34,199
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	3	2/15/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $35,141

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	2	5/2/2022	NON-COMPETING CONTINUATION	$717
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	002	2	7/18/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	2	11/11/2021	NON-COMPETING CONTINUATION	$46,036
														Subtotal = $46,752

Issue Date FY: 2020 ( Subtotal = $45,520 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	1	9/1/2020	NEW	$45,520
														Subtotal = $45,520

Grand Total All Awards = $103,615

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Investigating a molecular basis for Alzheimer's disease subtypes using multiomic data integration and machine-learning

Award Number: F31AG069441

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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