# Impact of APOE deficiency on HPA axis function and cognition

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $669,189

## Abstract

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 gen...

## Key facts

- **NIH application ID:** 10800820
- **Project number:** 1R01AG082315-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Richard S Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $669,189
- **Award type:** 1
- **Project period:** 2023-12-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800820

## Citation

> US National Institutes of Health, RePORTER application 10800820, Impact of APOE deficiency on HPA axis function and cognition (1R01AG082315-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10800820. Licensed CC0.

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