# APOE4 promotes pathogenesis in a mouse model of cancer chemotherapy-induced cognitive impairment

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2024 · $386,920

## Abstract

Cancer chemotherapy causes marked cognitive impairment that involves deficits in learning & memory,
attention, and executive functions. The best characterized genetic risk factor for chemotherapy induced
cognitive impairment (CICI) is the E4 allele of APOE, which is also the strongest genetic risk factor for
Alzheimer’s disease (AD). This commonality of risk provides a powerful opportunity to define mechanisms of
the effects of APOE4 on cognitive dysfunction across conditions. We have developed a mouse model of
APOE4-related CICI showing strong chemotherapy-induced cognitive effects in the APOE4 mice but not
APOE3 mice, providing independent confirmation of this genetic risk in humans. We hypothesize that
chemotherapy induces CNS damages related to APOE functions. We are testing specific mechanisms of
APOE4-related vulnerability in four specific aims: Aim 1: Determine how chemotherapy affects pathogenic
processes of Alzheimer’s disease. We will use a mouse model of amyloid influenced by the different APOE
alleles (EFAD mice), to define mechanisms of chemotherapy on AD pathogenesis. We will expose cohorts of
E3FAD and E4FAD mice to a chemotherapy regimen or vehicle control, and determine which AD pathological
pathways are affected (A levels, phospho-tau, microglial and astrocytic activation, neuronal and synaptic loss,
and hippocampal atrophy). Aim 2: Define mechanisms of APOE4-related chemotherapy sensitivity in a
non-AD model. The APOE4 knock-in mouse model allows testing for CNS alterations that may underlie CICI
in cognitively healthy individuals. We will test CNS mechanisms already identified in relation to the APOE4
genotype for exacerbation after chemotherapy, including: inflammation; neurogenesis; DNA damage; glial
senescence; blood brain barrier breakdown; and oxidative damage. Aim 3: Identify specific chemotherapies
associated with lower risks of cognitive impairment. We will use our sensitive and reproducible APOE4
mouse model to test whether some cancer chemotherapeutic approaches are safer than others. We will treat
the susceptible APOE4 mice with four of the common cancer chemotherapies with different mechanisms of
action. Aim 4: Test therapeutic approaches to prevention of chemotherapy-induced cognitive
impairments. Identification of APOE-related mechanisms allows the targeted identification of preventative
approaches. We initially will test an agent for increasing lipidated APOE levels (bexarotene), and an anti-
inflammatory agent (an antagonist of the receptor for advance glycation endproducts (RAGE)). Together, these
Aims will identify mechanisms underlying the risk of CICI in the large portion of the population carrying the
APOE4 allele. In addition, the acute nature for the onset of CICI allows a more controlled approach for studying
the negative effects of APOE4 in vivo, compared to only studying gradual processes of aging and
neurodegeneration. Findings can be easily translated to clinical situations in terms of identifying ...

## Key facts

- **NIH application ID:** 10765740
- **Project number:** 5R01AG067258-05
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** G WILLIAM REBECK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,920
- **Award type:** 5
- **Project period:** 2020-05-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765740

## Citation

> US National Institutes of Health, RePORTER application 10765740, APOE4 promotes pathogenesis in a mouse model of cancer chemotherapy-induced cognitive impairment (5R01AG067258-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10765740. Licensed CC0.

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