Wednesday, July 2, 2025 7/2/2025

Investigating the role of an EIF2B3 variant as an Alzheimer's disease risk modifier

Award Number: F32AG082483
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/23/2023
PERIOD OF PERFORMANCE END DATE: 03/22/2026

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Investigating the role of an EIF2B3 variant as an Alzheimer's disease risk modifier - Project Summary Human genetic studies provide a powerful approach to identify genes and pathways associated with Alzheimer's disease (AD). Apolipoprotein E isoform 4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease. Despite the strong effect of APOE4 on AD risk, a wide range of clinical outcomes exist within APOE4 carriers: some can develop cognitive impairment as early as 30 years of age while other carriers remain cognitively normal beyond 100 years. The large range in clinical manifestation amongst APOE4 carriers suggests that there are genetic variants that modulate APOE-associated risk. To investigate this hypothesis, we conducted stratified genome-wide association studies of APOE4 carriers at the extremes of age at onset distribution to identify variants that modify risk. We identified a single variant in EIF2B3 encoding the amino acid substitution S404A as a candidate risk modifier. eIF2B3 is a subunit of eIF2B, a guanine exchange factor (GEF) for eIF2 that is involved in translational control and the integrated stress response. Our lab has recently shown that APOE4 induces a constitutively upregulated ISR and aberrant protein translation in murine and human iPSC-derived microglia, demonstrating that APOE4 alone can lead to increased levels of cellular stress1,2. Furthermore, EIF2B2, another eIF2B subunit, is an AD risk gene identified in AD GWAS3. The overall goal of this proposal is to directly test the hypothesis that EIF2B3 variants modulate APOE4-associated risk by dysregulating the ISR and thus alter microglial cell function in the context of disease. In Aim 1, I will combine cell-free in vitro fluorescent GEF assays and structural chemistry to determine the effects of EIF2B3S404A directly on eIF2B structural integrity and enzymatic activity, in the absence of cellular stress. Aim 2 will determine the impact of EIF2B3S404A on APOE4 microglia cell function in vitro using human induced pluripotent stem cell (iPSCs)- derived microglia and live-cell imaging in the context of disease-related stressors. Lastly, in Aim 3, I will employ novel xenotransplantation methods involving direct injection of human microglia precursor cells into the mouse brain to evaluate the effect of EIF2B3S404A on APOE4 microglia cell function in vivo and in the context of disease. Together, the results here will confirm or refute the hypothesis that EIF2B3 variants modulate APOE4-associated risk by altering microglial cell function. Throughout the project, I will test the efficacy of an ISR inhibitor (ISRIB) drug at alleviating EIF2B3S404A -induced effects on EIF2B activity in vitro and in microglia in vitro and in vivo. The work here has the potential to greatly impact public health through understanding the way in which variants affect immune cell function and modify disease risk and by potentially identifying a novel drug for the treatment of AD. The fellowship training plan proposed here will provide me with the technical skills, scientific knowledge, critical thinking skills gained from Dr. Alison Goate's mentorship and the collaborative environment at the Icahn School of Medicine at Mount Sinai at large, equipping me with the necessary skills for a successful transition to a career as an independent scientist.


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 = $81,040 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	3	3/12/2025	NON-COMPETING CONTINUATION	$79,756
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	3	6/23/2025	NON-COMPETING CONTINUATION	$1,284
														Subtotal = $81,040

Issue Date FY: 2024 ( Subtotal = $74,284 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	2	5/2/2024	NON-COMPETING CONTINUATION	$4,784
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	2	3/12/2024	NON-COMPETING CONTINUATION	$69,500
														Subtotal = $74,284

Issue Date FY: 2023 ( Subtotal = $69,080 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	001	1	3/23/2023	NEW	$0
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	1	3/23/2023	NEW	$69,080
														Subtotal = $69,080

Grand Total All Awards = $224,404

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Investigating the role of an EIF2B3 variant as an Alzheimer's disease risk modifier

Award Number: F32AG082483

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/23/2023

PERIOD OF PERFORMANCE END DATE: 03/22/2026

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