Monday, June 30, 2025 6/30/2025

Individual Predoctoral Fellowship

Award Number: F31AG084295
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/02/2024
PERIOD OF PERFORMANCE END DATE: 02/01/2027

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Individual Predoctoral Fellowship - ABSTRACT Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tau tangles (NFTs) which together contribute to neuroinflammation, neurodegeneration, and often cognitive decline. Down syndrome (DS) is the result of having three copies of chromosome 21 (T21) from conception. The Aβ peptide is a cleavage product of the amyloid precursor protein (APP) which is encoded by the APP gene. Given that the APP gene resides on chromosome 21, all people with DS accumulate higher levels of Aβ peptide in their brains. Accordingly, adults with DS will develop AD pathology (DS-AD), and many go on to develop clinical dementia. DS-AD has documented pathological differences from typical AD, including accelerated Aβ and tau accumulation and a more heterogeneous Aβ plaque composition. While there are numerous genetic and environmental contributors to AD risk, the APOE gene, and especially the ε4 variant (APOE4), has been identified as the greatest risk factor for typical AD besides age itself. Inheritance of APOE4 also significantly increases risk for AD and cognitive decline in individuals with DS. Cohort studies in people with DS have found an overall increased AD risk conferred by APOE4, but investigations of the mechanistic role of APOE4 in people with DS are lacking. Clearly, there is an urgent need for studies interrogating the mechanism of increased risk of AD for people with DS carrying APOE4. The overall goal of this proposal is to elucidate the role of the APOE4 genotype in the development of DS-AD and assess the potential of apoE4-drive Aβ fibrilization as a therapeutic target. Specifically, I will identify APOE4- driven mechanisms and pathways that contribute to the development of DS-AD neuropathologies and assess the efficacy of small molecular inhibitors of apoE and/or Aβ in alleviating these pathologies. To accomplish these goals, I will develop novel human induced pluripotent stem cell (hiPSC)-based models of DS-AD that carry APOE4. I will generate multiple human neural cell types and cerebral organoids (COs) from the hiPSCs to determine the specific effects of APOE4 in these models of the developing and aging human DS-AD brain. I will evaluate six validated small molecule drugs that have been shown to prevent and/or reverse apoE4-catalyzed Aβ fibrillization in my CO model system. My overall hypothesis is that APOE4 will accelerate and enhance the development of AD neuropathologies in hiPSC-based models of DS-AD and can be targeted with small molecule apoE inhibitors to alleviate those AD phenotypes.


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 = $37,121 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	2	2/14/2025	NON-COMPETING CONTINUATION	$36,577
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	001	2	6/23/2025	NON-COMPETING CONTINUATION	$544
														Subtotal = $37,121

Issue Date FY: 2023 ( Subtotal = $35,361 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	1	8/2/2023	NEW	$35,361
														Subtotal = $35,361

Grand Total All Awards = $72,482

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Individual Predoctoral Fellowship

Award Number: F31AG084295

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/02/2024

PERIOD OF PERFORMANCE END DATE: 02/01/2027

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