Identification of the immune-specific genetic architecture common to
Alzheimer?s disease risk and rate of progression 
   Lead Investigator:    Oscar Harari
   Institution      :    Washington University School of Medicine
   E-Mail           :    harario@wustl.edu
   Proposal ID      :    1126



   Proposal Description:
   Aim 1. To identify genetic factors associated with the Alzheimer?s Disease      rate of progression                                                               We will access longitudinal clinical evaluations (CDR-SB) from the NACC           repositories with GWAS data (or generate genotypes otherwise) to identify common variants, genes and pathways associated with AD rate of progression. To maximize the statistical power, we will combine the data to perform a joint one-stage GWAS and meta-analysis with all individuals from ADNI and Knight-ADRC. Furthermore, we will analyze whether the most significant single nucleotide polymorphisms (SNPs) for rate of progression show association with AD risk, age at onset or CSF biomarkers and imaging biomarkers.                            Aim 2. To determine the extent of overlap between the genetic architectures of AD and other aspects of disease                                                                           We will calculate PRSs based on the GWAS results for AD risk, rate of progression, age at onset, CSF A#946, tau and p-tau GWAS. These scores will be then incorporated in models to test the association of the AD risk and other disease modifiers. We will evaluate whether the genetic architecture of rate of progression of late-onset AD is also share in ADAD, by analyzing the data from the Dominantly Inherited Alzheimer Network (DIAN)                                                          Aim 3. To analyze whether genetic factor that modulate AD risk in immune-specific pathways are also associated with rate of progression.                                              We will calculate polygenic risk scores for AD, rate of progression and previously mentioned disease aspects focusing only on the genes and pathways associated with the immune response, and compare these scores to identify whether genetic factors harbored in immune-response genes and pathways modulate AD risk, rate of progression, and additional dise