Genome-wide association studies (GWAS) have identified APOE2 allele as linked to exceptional longevity, with carriers exhibiting a reduced risk of Alzheimer's disease (AD). Apolipoprotein E (APOE), a glycoprotein involved in lipid transport, has three major alleles. However, alterations in lipid metabolism alone do not fully explain APOE2's protective effects. In contrast, APOE4 is the strongest genetic risk factor for AD. To investigate how APOE2 promotes neuronal longevity and confers neuroprotection, we generated human isogenic APOE iPSC-derived models of both inhibitory GABAergic and excitatory neurons. In GABAergic neurons, APOE alleles differentially influenced endogenous DNA damage, DNA repair, and neuronal motility. Single-cell RNA sequencing revealed APOE4-specific gene expression signatures associated with AD, whereas APOE2 GABAergic neurons were enriched for DNA repair and signaling pathways. Consistent with this, APOE2 neurons exhibited significantly lower levels of DNA damage. APOE4 GABAergic neurons exhibit increased expression of repetitive ribosomal RNA, which is associated with DNA damage and cellular senescence. To determine whether the effects extended to excitatory neurons, we used a separate human model of Ngn2-induced glutamatergic neurons, and found that APOE2 excitatory neurons were more resistant to cellular senescence and DNA damage than isogenic APOE3 and APOE4 neurons. Similarly, we found human APOE2-targeted replacement mice exhibited less nucleolar enlargement and increased nuclear Lamin A/C, Hmgb1, and H3K9me3 compared to APOE4 counterparts. Together, our findings identify DNA repair and suppression of senescence-associated processes as key mechanisms by which APOE2 is associated with neuronal resilience, providing mechanistic insight into its association with exceptional longevity and protection against AD.
