Neurogenomics of Alzheimer's Disease and Aging

Summary

Principal Investigator: Dietrich Stephan
Abstract: DESCRIPTION (provided by applicant): Alzheimer's disease (AD) affects a large proportion of the world's population and is primarily a disease of old age. There is little known about the early molecular pathogenesis of AD leading to the characteristic dementia. Increased knowledge of the etiologic processes leading to dementia would allow improved diagnostics and targeted therapeutics. This proposal is multifaceted and seeks to elucidate 1) what differentiates AD from normal aging processes and other dementias of old age, 2) why individuals with certain genetic backgrounds (ApoE4 alleles) are more likely to become affected (inter-individual differences), 3) and what happens at the cellular and subcellular level in response to dementia-inducing stimuli (plaques and tangles)(intra-individual differences). Taken together the expression profiling data set generated on laser capture microdissected (LCM) cells from carefully stratified patient cohorts should provide unique insight into the AD phenotype. Specific hypotheses related to energy metabolism will be validated by multiple techniques (by immunohistochemistry on independent tissues and at the functional level using neuronal cell cultures and siRNAs). These results will be made available to the general public within 6 months of generation via the most established relational database for array data, the NINDS/NIMH array consortium repository. The applicants are uniquely qualified to perform a large-scale collaborative study of this type. Working closely in collaboration with 3 Alzheimer's Disease Centers (ADCs), the PIs will have access to tissue sections from the appropriate cohorts. The use of tissue sections (as opposed to large heterogeneous pieces of brain) and LCM as the starting reagents for the expression profiling will allow generation of high quality data while not depleting the banked national resource of brains. The PI is the Chairman of a National consortium of expression profiling facilities which generate extremely high quality data on large numbers of neurological phenotypes. Integration of this data set into that repository will increase the value of the AD data set exponentially because of the increased number of comparisons which can be generated using pre-existing data. The group also has access to sophisticated validation technologies. In all, the partnership of leaders in the AD field, the national resources within the ADCs, and the genomics expertise at TGen should allow rapid progress in understanding the etiology of AD dementia.
Funding Period: 2003-09-30 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. pmc Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations
    S H Y Chou
    Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT, Boston, Mass, USA
    Cerebrovasc Dis 36:181-8. 2013
  2. pmc Genetic susceptibility for Alzheimer disease neuritic plaque pathology
    Joshua M Shulman
    Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Jan and Dan Duncan Neurological Research Institute, Texas Children s Hospital, Houston
    JAMA Neurol 70:1150-7. 2013
  3. pmc Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    Physiol Genomics 28:311-22. 2007
  4. pmc A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline
    Brendan T Keenan
    Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Hum Mol Genet 21:2377-88. 2012
  5. pmc A genome-wide scan for common variants affecting the rate of age-related cognitive decline
    Philip L De Jager
    Institute for the Neurosciences, Department of Neurology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Neurobiol Aging 33:1017.e1-15. 2012
  6. pmc CR1 is associated with amyloid plaque burden and age-related cognitive decline
    Lori B Chibnik
    Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women s Hospital, Boston, MA, USA
    Ann Neurol 69:560-9. 2011
  7. pmc Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    Neuroimage 54:1896-902. 2011
  8. pmc Evidence for an association between KIBRA and late-onset Alzheimer's disease
    Jason J Corneveaux
    Translational Genomics Research Institute TGen, Neurogenomics Division, Phoenix, AZ 85004, USA
    Neurobiol Aging 31:901-9. 2010
  9. pmc Neuronal gene expression in non-demented individuals with intermediate Alzheimer's Disease neuropathology
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    Neurobiol Aging 31:549-66. 2010
  10. pmc High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation
    David O Azorsa
    Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, Arizona 85251, USA
    BMC Genomics 11:25. 2010

Scientific Experts

  • Eric Reiman
  • Philip L De Jager
  • Winnie S Liang
  • David O Azorsa
  • Travis L Dunckley
  • Jason J Corneveaux
  • Joshua M Shulman
  • Lori B Chibnik
  • Matthew J Huentelman
  • Brendan T Keenan
  • David A Bennett
  • Denis A Evans
  • Amanda J Myers
  • Keith D Coon
  • S H Y Chou
  • Julie A Schneider
  • Kewei Chen
  • Dong Tran
  • John A Hardy
  • Dietrich A Stephan
  • Andreas Papassotiropoulos
  • J M Shulman
  • Pradeep Thiyyagura
  • Cristin McCabe
  • A S Buchman
  • Adam Fleisher
  • E A Secor
  • Nikolaos A Patsopoulos
  • J Schneider
  • D A Bennett
  • Lei Yu
  • Auttawut Roontiva
  • B T Keenan
  • April N Allen
  • Mert R Sabuncu
  • Cynthia A Lemere
  • Towfique Raj
  • Anne Nicholson-Weller
  • Robert S Wilson
  • Sue E Leurgans
  • Christopher B Heward
  • Aron S Buchman
  • Cristin Aubin
  • Wendy Lee
  • Ron C Petersen
  • Richard J Caselli
  • Victoria L Zismann
  • Diane Hu-Lince
  • Joseph Rogers
  • Jennifer A Webster
  • Daniel Bandy
  • Rivka Ravid
  • John V Pearson
  • Andrew Grover
  • Michael L Hutton
  • Heike Kolsch
  • Diego Mastroeni
  • Sigrid B Sando
  • David W Craig
  • Thomas G Beach
  • Frank Jessen
  • Jan O Aasly
  • Gene E Alexander
  • Reinhard Heun
  • Stacey Melquist
  • Keta D Joshipura
  • Wallace W Tourtellotte
  • Stephanie J Yee
  • Floyd F Petersen
  • Claudius Mueller
  • Andrew M Siegel
  • Wolff M Kirsch
  • Rashed M Nagra

Detail Information

Publications16

  1. pmc Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations
    S H Y Chou
    Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT, Boston, Mass, USA
    Cerebrovasc Dis 36:181-8. 2013
    ....
  2. pmc Genetic susceptibility for Alzheimer disease neuritic plaque pathology
    Joshua M Shulman
    Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Jan and Dan Duncan Neurological Research Institute, Texas Children s Hospital, Houston
    JAMA Neurol 70:1150-7. 2013
    ..While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques...
  3. pmc Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    Physiol Genomics 28:311-22. 2007
    ..These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders...
  4. pmc A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline
    Brendan T Keenan
    Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Hum Mol Genet 21:2377-88. 2012
    ..We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q...
  5. pmc A genome-wide scan for common variants affecting the rate of age-related cognitive decline
    Philip L De Jager
    Institute for the Neurosciences, Department of Neurology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Neurobiol Aging 33:1017.e1-15. 2012
    ....
  6. pmc CR1 is associated with amyloid plaque burden and age-related cognitive decline
    Lori B Chibnik
    Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women s Hospital, Boston, MA, USA
    Ann Neurol 69:560-9. 2011
    ..We leveraged available neuropsychological and autopsy data from 2 cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology...
  7. pmc Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    Neuroimage 54:1896-902. 2011
    ..It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk...
  8. pmc Evidence for an association between KIBRA and late-onset Alzheimer's disease
    Jason J Corneveaux
    Translational Genomics Research Institute TGen, Neurogenomics Division, Phoenix, AZ 85004, USA
    Neurobiol Aging 31:901-9. 2010
    ..034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD...
  9. pmc Neuronal gene expression in non-demented individuals with intermediate Alzheimer's Disease neuropathology
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    Neurobiol Aging 31:549-66. 2010
    ..We also provide this high-quality, low post-mortem interval (PMI), cell-specific, and region-specific NDAD/AD reference data set to the community as a public resource...
  10. pmc High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation
    David O Azorsa
    Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, Arizona 85251, USA
    BMC Genomics 11:25. 2010
    ..Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments...
  11. pmc Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004, USA
    Proc Natl Acad Sci U S A 105:4441-6. 2008
    ..Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain...
  12. pmc Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set
    Winnie S Liang
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA
    Physiol Genomics 33:240-56. 2008
    ..We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource...
  13. pmc GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers
    Eric M Reiman
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
    Neuron 54:713-20. 2007
    ..Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology...
  14. ncbi Linking brain imaging and genomics in the study of Alzheimer's disease and aging
    Eric M Reiman
    Banner Alzheimer s Institute, Department of Psychiatry at the University of Arizona, Arizona Alzheimer s Consortium, Phoenix, Arizona 85006, USA
    Ann N Y Acad Sci 1097:94-113. 2007
    ..Finally, I illustrate the push-pull relationship between brain imaging, genomics research, and other neuroscientific research in the study of AD and aging...
  15. pmc Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease
    Keith D Coon
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    J Alzheimers Dis 9:225-33. 2006
    ..Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder...
  16. pmc Gene expression correlates of neurofibrillary tangles in Alzheimer's disease
    Travis Dunckley
    Neurogenomics Division, Translational Genomics Research Institute, 445 North 5th Street, Phoenix, AZ 85004, USA
    Neurobiol Aging 27:1359-71. 2006
    ..Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD...