# Aging, Rather than Genotype, Is the Principal Contributor to Differential Gene Expression Within Targeted Replacement APOE2, APOE3, and APOE4 Mouse Brain

## TL;DR

This study shows that aging, not APOE genotype, is the main driver of gene expression changes in the brain, with APOE4 worsening the aging effect.

## Contribution

The study demonstrates that aging, not APOE genotype, is the primary driver of gene expression changes in humanized APOE mice.

## Key findings

- Over half of the differentially expressed genes were shared across APOE2, APOE3, and APOE4 genotypes, indicating aging-driven changes.
- APOE4 uniquely altered pathways related to aging, while APOE2 and APOE3 had fewer unique pathway changes.
- Aging-induced gene expression changes involved metabolism, synaptic function, and protein synthesis.

## Abstract

Background: Apolipoprotein E (APOE) is the strongest genetic risk determinant for late-onset Alzheimer’s disease (AD). The APOE3 allele is risk-neutral, the APOE4 allele increases the risk of developing AD, and the APOE2 allele is neuroprotective. Methods: We utilized RNA sequencing of hemi-brains from a mouse model homozygous for each of these humanized APOE alleles to study gene expression profiles between mice aged 12 months of age (MO) and 18 MO, independent of β-amyloid and tau pathology. Results: More than half of the differentially expressed genes (DEGs) within each genotype were shared with at least one other APOE allele, including 1610 DEGs that were shared across the three genotypes. These DEGs represent changes driven by aging rather than APOE genotype. Aging induced DEGs and biological pathways involving metabolism, synaptic function, and protein synthesis, among others. Alterations in these pathways were also identified by DEGs unique to APOE4, suggesting that the APOE4 allele drives the aging phenotype. In contrast, fewer pathways were identified from DEGs unique to APOE2 or APOE3. Conclusions: Transcriptomic results suggest that the most significant impact on brain-level expression changes in humanized APOE mice is aging and that APOE4 exacerbates this process. These in vivo findings within an established model system are consistent with brain aging being the greatest risk factor for AD and suggest that APOE4 expression promotes an aging phenotype in the brain that interacts with, and contributes to, aging-driven AD risk. Results reinforce the impact age and APOE allele contribute to AD and age-related neurodegeneration, and foster greater mechanistic understanding as well as inform therapeutic intervention.