Assessing the risk of APOE #9494 in AD patients of difference ancestries

 
   Lead Investigator:    Madison Parks
   Institution      :    Mount Sinai  Icahn School of Medicine
   E-Mail           :    madison.parks@mssm.edu
   Proposal ID      :    952



   Proposal Description:
   (1) The APOE #9494 allele is a major risk factor for Alzheimer Disease (AD). The  human APOE gene exists as three polymorphic alleles?#9492, #9493 and #9494?which  have a frequency of 8.4, 77.9 and 13.7, respectively. However, the frequency  of the #9494 allele is dramatically increased to ~40 in patients with AD of  European ancestry. Few studies have examined the role of APOE in other  ancestries such as African American, Hispanic and Asians. Early studies with  African American cohorts reported inconsistent results (Farrer et al., 1997  Sahota et al., 1997). However, a meta-analysis has reported that there is a  risk factor for AD in African American populations with an odds ratio (OR) of  2.31 (Reitz et al., 2013). The reasons for differences in #9494 risk between  different ancestries remain unclear. We hypothesize that the difference in #9494  frequencies among AD in populations of non-European ancestry are due to  environmental factors or modifiable risk factors (i.e., as vascular risk  factors such as a history of hypertension, diabetes, and high cholesterol  levels). Our goal here is to understand the risk of APOE #9494 in AD patients of  difference ancestries including European, African American, Latinos and East  Asian.  (2) The objective of this proposal is to study the frequencies of APOE #9492, #9493  and #9494 in individuals of European, African American, Latino and Asian  ancestry. We will analyze whether the one or two copies of the APOE #9494 allele  were significant risk factors for incident AD within each ancestry. Secondly,  we will use Mendalian Randomization method and admixture based method (see Raj  et al. 2016 Neurology Genetics) to identify genetic associations between  potentially modifiable risk factors and APOE in Alzheimer Disease. The analyses  proposed here will allow us to explore the role of APOE and modifiable risk  factors in distinct human populations so that interventions to mitigate AD can  be more effectively targeted. At the