Investigating an African American-specific APOE genetic variant using hiPSC

PROJECT SUMMARY ABSTRACT
African Americans are at a significantly elevated risk of Alzheimer’s disease (AD) compared to the non-Hispanic
white population. Yet, the underlying mechanisms of this health disparity are significantly understudied. Recently,
a variant in Apolipoprotein E (APOE), APOE R145C, was identified as significantly increasing the risk of AD
among individuals of African ancestry. Despite this association, the underlying mechanisms of how the presence
of this APOE variant exacerbates AD onset and progression in aging adults have yet to be elucidated. As such,
we will use our collective experience in stem cell bioengineering, neurodegenerative disease modeling, and
genome editing to elucidate the potential mechanisms by which the APOE R145C variant modulates AD risk. To
that end, in the first aim, we will use our recently developed highly efficient gene editing approach to introduce
the APOE R145C variant into isogenic human induced pluripotent stem cells (hiPSCs) from both non-demented
control (NDC) and AD patients including those derived from African American subjects. In turn, in the second
aim, biochemical, cellular, and genetic analysis of neuronal, astrocytic, and microglia cultures will be used to
determine the effect of the APOE R145C variant on the presence of AD-related phenotypes. In particular, we
will determine if APOE R145C exerts its risk modifying effects through (i) modulation of Aβ processing, secretion,
or uptake and (ii) alteration in tau hyperphosphorylation and uptake. In addition, whole transcription analysis will
be used to identify signaling pathways and transcriptional targets that are modified by the presence of the APOE
R145C variant and disease status. Overall, the data obtained as part of this proposal will set the stage for future
hypothesis-testing studies to probe the mechanisms by which the African American-associated APOE R145C
variant accelerates AD onset. Such investigations will have a significant impact on the design of molecularly
targeted therapies to treat AD in the high-risk African American population.

Grant Number: 5R21AG085395-02
NIH Institute/Center: NIH
Principal Investigator: DAVID BRAFMAN