Dissecting Genetic and Non-genetic Heterogeneity in Predisposition to
Alzheimer's Disease and Vascular Traits in Pleiotropic Context 
   Lead Investigator:    Alexander Kulminski
   Institution      :    Duke University
   E-Mail           :    kgauthreaux@gmail.com
   Proposal ID      :    1617



   Proposal Description:
   The objective of this project is to identify personalized genetic and non-genetic profiles of risk of, protection against, and resilience to Alzheimer?s disease (AD) and AD-related dementias (AD/ADRD) and vascular diseases in the disease-specific and pleiotropic contexts. In addition to GWAS data, this project will use the whole exome sequencing data to nominate novel pleiotropic loci. This project will include ADSP-linked phenotypic data from NACC to complement AD by vascular traits measured in the same people. Genetic data will be imputed to create the same genotyping set in each study for cross-platform analyses.    Aim 1 will identify specific and pleiotropic loci for AD/ADRD and vascular traits from the exome-wide association study (EWAS) by performing pleiotropic EWAS focused on AD/ADRD, cardiovascular diseases (CVD) and AD/ADRD risk factors and examining the role of sex and races/ethnicities.     Aim 2 will dissect heterogeneity leveraging the analysis of molecular signatures defined as differences in linkage disequilibrium (LD) patterns in affected and unaffected subjects. We will examine: (i) molecular signatures of AD/ADRD and CVDs in the prioritized loci and a potential role of rare variants and (ii) the difference in LD structures between younger and older subjects to identify the potential impact of survival selection in affected subjects. We will dissect heterogeneity attributed to several exogenous and endogenous AD/ADRD-related factors, and identify commonalities between the signatures of AD/ADRD, other diseases from Aim 1, and AD/ADRD risk factors. We will identify molecular signatures of AD/ADRD resilience and potentially causal risk factors for AD/ADRD leveraging the analysis of LD structures in younger subjects.     Aim 3 will identify personalized genetic profiles of AD/ADRD-specific and pleiotropic risks, protection, and resilience using rigorous methods. We will use individual SNPs identified in Aim 1 and SNPs from the molecular signature