Wednesday, December 31, 2025 12/31/2025

Impact of APOE deficiency on HPA axis function and cognition

Award Number: R01AG082315
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

Group Awards By:

View Award Description

Impact of APOE deficiency on HPA axis function and cognition - The E4 allele of apolipoprotein E (APOE4) is the most common genetic risk for Alzheimer's Disease (AD). Given the function of apolipoproteins in the transport of lipids and cholesterol, it is believed that individuals with APOE4 have impaired lipid metabolism leading to atherosclerosis and dementia. However, the role of APOE4 on Alzheimer's Disease and dementia remains unclear, and there are likely to be additional roles for APOE4 beyond its putative role in lipid transport. There is emerging evidence that the hypothalamic pituitary adrenal (HPA) axis, which is necessary for mounting the fight-or flight stress response, may be dysregulated in individuals with the APOE4 allele. Specifically, APOE4-carrying individuals and mice with APOE deficiency both exhibit elevated levels of baseline stress hormones as well as pronounced stress response following exposure to stress. There is already substantial evidence linking chronic exposure to stress and subsequent repetitive HPA axis activation to AD. Aging, the primary risk factor for AD, can be defined as the body's lifelong effort to maintain allostasis, which refers to the mechanism engaged by the body to maintain homeostasis during cumulative “wear and tear” from various forms of environmental stressors. As such, the failure to achieve allostasis results in increased “allostatic load” in the form of elevated levels of the catabolic stress hormone cortisol. Chronically elevated levels of cortisol have long been linked to cognitive impairment and reduced brain volumes, which are the hallmark symptoms of AD. Taken together, these studies raise the possibility that APOE deficiency may precipitate AD- related symptoms by overstimulating the HPA axis and causing excess “wear and tear” across age. We will explore this potential interaction between the APOE gene and the HPA axis by using mice harboring the humanized APOE3 protective allele or the APOE4 risk allele and subjecting them to chronic stressors. We will document their stress hormone and lipid levels and correlate them to scores on tests of learning and memory. This will help us determine whether cortisol or lipid levels mediate the effect of APOE deficiency on cognition. To find further evidence of HPA axis dysregulation, we will examine stable epigenetic changes in the function of genes that are associated with the HPA axis. We will examine an epigenetic modification known as DNA methylation that has been linked to allostatic load in mice exposed to stress hormones. Identification of these changes in stress exposed APOE3/APOE4 mice will provide strong evidence for HPA axis dysregulation in APOE4 mice. Finally, we will pharmacologically and genetically alter the ability of APOE4 mice to mount a stress response. We will measure the effect of using inhibitors and modulators of two primary proteins that regulate stress hormone signaling on learning and memory. Genes that encode these two proteins will be epigenetically manipulated using a modified gene-editing tool to further corroborate our hypothesis. Proving our hypothesis will not only lead to a paradigm shift in our view of the role that APOE plays in AD, but also provide novel therapeutic strategies that are much needed for the prevention and treatment 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: 2026 ( Subtotal = $645,216 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	3	12/16/2025	NON-COMPETING CONTINUATION	$645,216
														Subtotal = $645,216

Issue Date FY: 2025 ( Subtotal = $701,075 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	2	11/15/2024	NON-COMPETING CONTINUATION	$643,845
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	001	2	8/13/2025	NON-COMPETING CONTINUATION	$57,230
														Subtotal = $701,075

Issue Date FY: 2024 ( Subtotal = $669,189 )
2024	2024	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	1	11/3/2023	NEW	$669,189
														Subtotal = $669,189

Grand Total All Awards = $2,015,480

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Impact of APOE deficiency on HPA axis function and cognition

Award Number: R01AG082315

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer