Genetics of Early-Onset Alzheimer?s Disease

 
   Lead Investigator:    Kelly Nudelman Liana Apostolova
   Institution      :    Indiana University
   E-Mail           :    kholohan@iu.edu
   Proposal ID      :    1004



   Proposal Description:
   While the risk of Alzheimer?s disease (AD) increases with advancing age, approximately 5 of AD patients develop symptoms before age 65 (~280,000 Americans). Patients with early-onset Alzheimer?s disease (EOAD), occurring before the age of 65, are an understudied segment of the AD patient population, and many treatment studies exclude these younger individuals.   Of the two major North American AD consortia, ADNI includes only a few EOAD cases all with a ?typical? amnestic presentation and DIAN focuses solely on autosomal dominant AD (ADAD). ADAD is driven by mutations in three genes, the amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). Fewer than 10 of EOAD patients carry a known mutation in APP or PSEN1/2, and <50 carry the APOE4+ risk allele. Still studies suggest high heritability in EOAD in the absence of known mutations or APOE4+, signifying that this population may be enriched for novel genetic risk factors. Whole genome sequencing (WGS) will be necessary to identify additional genes with concentrations of rare variants associated with EOAD. Identification of these variants and genes will also inform the study of the genetics of late-onset AD (LOAD), as it is likely that individuals with LOAD have less deleterious mutations in some of the same genes. The goal of the Genetics of Early Onset AD (GEOAD) Study is to perform whole genome sequencing on EOAD to identify novel rare genetic variants associated with AD.  GEOAD will perform WGS on up to 4,000 EOAD cases with available DNA who are not enrolled in DIAN. The study will also leverage existing data. We plan to test variants of interest for association with variables available in the Uniform Data Set (UDS) for most participants, as well as biomarkers measured for subsets of patients such as the funded LEADS study of EOAD, which will include imaging and fluid biomarkers for 400 EOAD. We will also investigate genes and variants of interest in the AD Sequencing Project (ADSP), to