Exploring key factors determining age at onset of Alzheimers disease in
APOE4 carriers using a cell-based lineage reprogramming approach
 
   Lead Investigator:    Julia TCW
   Institution      :    Mt Sinai School of Medicine
   E-Mail           :    smonsell@uw.edu
   Proposal ID      :    545



   Proposal Description:
   Apolipoprotein E (APOE) is a risk factor for late-onset Alzheimer's disease (AD). Although homozygous APOE4/4 alleles increase AD risk by >10-fold, some elderly APOE4/4 carriers fail to develop dementia the mechanism by which some individuals escape disease is unknown. Here, we hypothesize that disease onset of APOE4/4 carriers is affected by protective variants and/or environmental factors, especially those that impact the global epigenetic signature of aging. To test this, we will derive human induced pluripotent stem cells (hiPSCs) from APOE4/4 carriers, and then engineer isogenic APOE3/3 control hiPSCs using a genome editing tool isogenic hiPSCs will be differentiated to astrocytes and neurons for molecular and functional characterization. We will also use a direct differentiation strategy, from APOE4/4 fibroblasts to neurons/astrocytes, where epigenetic signatures of aging will be preserved. Using RNAseq and DNA methylation analysis, we will examine whether gene expression and epigenetic changes distinguish elderly APOE4/4 carriers from APOE4/4 AD cases. In a parallel study, we are examining whole genome sequence for genetic variants that influence age at onset in APOE4/4 carriers. Together, genetic, epigenetic and cell-based functional approaches will enable us to better understand how the age at onset of AD in APOE4/4 individuals can be modified.