Dissecting the interaction between sex and APOE genotype in modulating AD risk

Although the majority of AD patients are sporadic (SAD), numerous studies have implicated biological sex and variation in the Apolipoprotein E (APOE) gene as two of the strongest factors that modulate risk of AD onset and age-related progression. Specifically, compared to the APOE3 allele, individuals carrying one copy of APOE4

have an increased AD risk by 4-fold and individuals carrying two copies have up to 15-fold higher probability of developing AD. Conversely, individuals with the APOE2 allele are 40 percent less likely to develop AD. Moreover, the risk-inducing effects of APOE4 have been shown to be augmented in female patients. Despite these

interactions, the cellular and molecular mechanisms of sex-based differences in APOE-related AD risk have not been precisely determined. Previously, we used isogenic human induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which APOE genotypes influences AD risk. In this proposal, we will build upon

this work to dissect the role sex plays as it relates to these APOE genotype-dependent effects. To that end, in the first aim of this proposal will use our highly efficient gene editing technology to introduce various APOE genotypes into isogenic hiPSC lines with different sex chromosome complements derived from the same genetic

background. In the second aim, we will employ these isogenic hiPSC lines in the context of neuronal, astrocytic, and microglia culture systems to determine the manner in which APOE and sex interact to (i) influence Aβ processing, secretion, and uptake, (ii) alter tau hyperphosphorylation, and (iii) regulate global transcriptional

changes that would influence AD risk. Overall, a more thorough understanding of the mechanisms by which APOE and biological sex interact to modulate likelihood of AD onset will have a significant impact on the design of therapeutic interventions.