Understanding the Protective Effect of an APOE E4-linked haplotype using
Integrative Bioinformatics Analysis 
   Lead Investigator:    Sudeshna Das
   Institution      :    Massachusetts General Hospital, Dept of Neurology
   E-Mail           :    sdas5@mgh.harvard.edu
   Proposal ID      :    1194



   Proposal Description:
   APOE E4 - defined by a pair of SNPs: rs429358 and rs7412 - is associated with a higher risk of developing Alzheimers Disease (AD). This risk, however, is mitigated in some E4 carriers who have the G allele of another SNP in the APOE locus (rs769449) (1). We propose to investigate the protective mechanisms of this APOE E4-linked haplotype with the two E4-defining polymorphisms and rs769449. Our goals are to study the protective effect of this haplotype with longitudinal data from NACC and genotype data from the ADGC.     We hypothesize that the allelic differences of rs769449 is manifested in clinical, physiological and neuropathological trait differences, and that understanding the risk variation in E4 carriers will shed further light on APOE E4 pathophysiology in AD. We aim to identify any association of rs769449 with clinical, neuropsychological and pathological features. We will assess the association of genetic variants of rs769449 with changes in clinical ratings, neuropsychological tests, biomarkers and predefined autopsy features using multivariate models in subjects with ADGC genotypes and ADC longitudinal UDS, within strata of APOE E4 gene dose.                                                References:  (1) Babenko VN, Afonnikov DA, Ignatieva EV, Klimov AV, Gusev FE, Rogaev EI. Haplotype analysis of APOE intragenic SNPs. BMC Neurosci. 201819(Suppl 1):16. Epub 2018/05/11. doi: 10.1186/s12868-018-0413-4. PubMed PMID: 29745836 PubMed Central PMCID: PMCPMC5998902