Genetic determinants of age-associated temporal lobe tauopathy

 
   Lead Investigator:    John Crary
   Institution      :    Columbia U
   E-Mail           :    jc2892@cumc.columbia.edu
   Proposal ID      :    446



   Proposal Description:
   Introduction. Neurofibrillary degeneration of the Alzheimer???s type is a well-recognized pathological process that occurs during aging as well as in Alzheimer disease (AD). Intriguingly some patients, develop marked temporal lobe tauopathy and an amnestic dementia in an Abeta-independent manner (Santa-Maria et al., 2012). Little is known about this entity, termed tangle-predominant dementia (TPD) among other names, despite the fact that it may be among the most common AD mimics (Beach et al., 2012). Recent studies have confirmed that a significant proportion of elderly subjects are positive for p-tau and neurodegeneration biomarkers, but negative for amyloid by PET imaging and/or CSF studies. Thus, there is a critical need to better understand TPD as it will facilitate clinical trials of Ab targeting therapeutics by improving diagnostic accuracy and provide a unique perspective on the mechanisms underlying neurofibrillary degeneration.    Aim 1. To identify genetic determinants of age-related temporal lobe tauopathy.  We will obtain specimens from 300 well-characterized male and female subjects (aged 65-100 yr) from the CUMC brain bank and five additional centers within the NIH AD Research Center (ADRC) brain bank network. Subjects will be carefully selected to exclude all other known causes of cognitive impairment and NFT, including neuritic Ab plaques. We will then measure temporal lobe NFT using quantitative and semi-quantitative measures (i.e., histological and biochemical) and then correlate these with genotypes obtained using the Illumina SNP chips.    We expect to pinpoint key genetic determinants in the pathogenesis of temporal lobe NFT.