# Resilience pathways modeling human longevity-promoting ApoE variants in induced pluripotent stem cells

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2021 · $879,592

## Abstract

PROJECT SUMMARY
Isoforms of ApoE modify the risk for developing Alzheimer’s disease (AD) or cardiovascular disease, and are
also associated with exceptional longevity. Specifically, the e2/e2 genotype is associated with exceptional
longevity while the e4 allele is negatively associated with longevity. The e4 variant of the ApoE gene is also a
major risk factor for AD and is associated with higher levels of Ab deposition in the brain. Correspondingly, the
ApoE e2 allele is associated with a lower risk of AD-related neurodegeneration. The mechanisms modulating
extended lifespan mediated by e2 compared to e3 and e4 genotypes are not clear. One hypothesis is that the
ApoE e2 allele is neuroprotective and compensates for neuronal dysfunction induced by misfolded
protein expression in aging and disease. In addition, the developmental program for the ApoE e2 allele
may be distinct from the ApoE e4 allele. This is based on a body of literature that suggests the ApoE
genotypes effect brain structure and gene expression beginning prenatal development and continuing into late
life. Our proposed studies will utilize isogenic induced pluripotent stem cells (iPSCs) engineered with
CRISPR/Cas9 to express the three isoforms of the ApoE protein (E2, E3 and E4). Using genetic engineering in
preliminary studies, we generated lines carrying e2/e2, e3/e3 and e4/e4 genotypes in control iPSCs and
Huntington’s Disease-HD-iPSCs. Recent advances in stem cell research suggest that iPSCs may provide novel
models of aging and diseases. We will investigate using stem cell models the role of the exceptional longevity
factor ApoE2 in aging and disease with the following Specific Aims: Specific Aim 1. We will characterize the
cellular and functional differences in isogenic iPSCs with e2/e2, e3/e3 and e4/e4 genotypes using a systems
biology approach. Specific Aim 2: To determine whether longevity-promoting ApoE variants enhance stress
resistance and survival and identify the pathways relevant to the neuroprotective effects of the various variants.
Specific Aim 3. We will determine if expression of ApoE2 or factors produced by ApoE cells provide increased
health span in aged mice. Overall, our approach synergizes a number of unique methodologies to determine
how naturally occurring genetic variants associated with Alzheimer’s disease modulate health span in multiple
tissues and potentially lifespan. Successful completion of our proposed studies may reveal mechanisms with
potential therapeutic exploitation for age-related disease and aging.

## Key facts

- **NIH application ID:** 10174668
- **Project number:** 5R01AG061879-04
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Lisa M Ellerby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $879,592
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174668

## Citation

> US National Institutes of Health, RePORTER application 10174668, Resilience pathways modeling human longevity-promoting ApoE variants in induced pluripotent stem cells (5R01AG061879-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10174668. Licensed CC0.

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