Modifier Genes that Influence Age at Onset or Protect Against Development of
Alzheimer's Disease (AD) 
   Lead Investigator:    Carlos Cruchaga
   Institution      :    Washington University St Louis
   E-Mail           :    cruchagc@psychiatry.wustl.edu
   Proposal ID      :    440


   Publications:


1  Rehker J, Rodhe J, Nesbitt RR, Boyle EA, Martin BK, Lord J, Karaca I, Naj A, Jessen F, Helisalmi S, Soininen H, Hiltunen M, Ramirez A, Scherer M, Farrer LA, Haines JL, Pericak-Vance MA, Raskind WH, Cruchaga C, Schellenberg GD, Joseph B, Brkanac Z
   Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants
   Journal Article  PLoS One,12:e0185777,2017,PMC5630132

   PUBLISHED





   Proposal Description:
   Although most cases of Alzheimer???s disease (AD) have an age at onset above age 80yrs the range in age at onset is huge with the earliest ages at onset occurring in individuals as young as the third decade of life while other individuals may live beyond one hundred years and remain cognitively normal. Even within specific risk groups, for example presenilin (PSEN) mutation carriers or Apolipoprotein E e4 carriers (APOE4), the range in age at onset can vary by several decades. Individuals from an extended Colombian kindred, who develop AD, all carry the PSEN1-E280A variant but the range in age at onset in this family has been reported to span three decades (35-62yrs)(Lendon et al., 1997). Similarly, individuals who carry an APOE4 allele may develop AD as early as 50 yrs while other individuals with this risk factor may be cognitively normal and older than 80yrs of age (Corder et al., 1993). We hypothesize that in human populations there are both risk and protective alleles that influence the age at onset of AD.  Support for this hypothesis comes from our knowledge of the known AD genes. APOE and amyloid precursor protein (APP) have both risk and protective alleles for AD. In the case of APOE these alleles are common (APOE4-risk APOE2-protective), whilst in APP risk and protective alleles appear to be rare (Goate and Hardy, 2012 Jonsson et al., 2012a).    The goal of this project is to identify novel genes and variants that influence age at onset or protect for Alzheimer???s Disease. To do this we plan generate whole-genome and whole-exome sequencing data (for APOE44 carriers), and perform a survival analyses.