Alzheimer?s disease (AD) is a complex multifactorial disease with the possible involvement of a number of genes. Although the APOE*4 allele has been identified as a strong susceptibility marker for AD, it is neither necessary nor sufficient to cause the disease. This indicates the involvement of additional genetic factors, which either alone or in conjunction with APOE*4, increase an individual?s risk of developing AD. Recent studies indicate that apolipoprotein D (apoD) is involved in the neurodegenerative as well as neuroregenerative processes. Our novel preliminary immunohistochemical and genetic data also provide strong evidence that apoD is involved in the pathogenesis of AD. The objectives of this study will be achieved by fulfilling the following specific aims: 1) to confirm our preliminary findings that apoD shows different patterns of immunoreactivity between normal and AD brains and that apoD and AD localize in plaques, we will examine several additional brains from normal and AD cases, 2) to examine the functional role of apoD in modifying AP fibril formation and its role in mediation of apoE- regulated A beta fibril formation in vitro, 3) to screen all exons, introns and 5? and 3? regions of the apoD gene by polymerase chain reaction (PCR), HPLC-based Wave DNA Fragment Analysis system and DNA sequencing in 1 00 autopsy confirmed AD cases (50 with APOE*4 and 50 without APOE*4) to identify and characterize genetic variation in the apoD gene. The association of the apoD genetic variation with the risk of AD will be evaluated in two case-control cohorts of U.S. whites and blacks. The proposed immunochemical, functional, molecular and genetic epidemiological studies will enable us to delineate the role of the apoD in the etiology of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG013672-06A2
Application #
6479179
Study Section
Special Emphasis Panel (ZRG1-SNEM-5 (02))
Program Officer
Miller, Marilyn
Project Start
1996-05-29
Project End
2005-04-30
Budget Start
2002-08-15
Budget End
2003-04-30
Support Year
6
Fiscal Year
2002
Total Cost
$262,120
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Chapuis, J; Hot, D; Hansmannel, F et al. (2009) Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease. Mol Psychiatry 14:1004-16
Figgins, Jessica A; Minster, Ryan L; Demirci, F Yesim et al. (2009) Association studies of 22 candidate SNPs with late-onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 150B:520-6
Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas (2009) No association of DAPK1 and ABCA2 SNPs on chromosome 9 with Alzheimer's disease. Neurobiol Aging 30:1890-1
Conley, Yvette P; Mukherjee, Ankur; Kammerer, Candace et al. (2009) Evidence supporting a role for the calcium-sensing receptor in Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet 150B:703-9
Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas (2008) No association of SORL1 SNPs with Alzheimer's disease. Neurosci Lett 440:190-2
Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas (2008) No association of dynamin binding protein (DNMBP) gene SNPs and Alzheimer's disease. Neurobiol Aging 29:1602-4
Ozturk, Ayla; Minster, Ryan L; DeKosky, Steven T et al. (2007) Association of tagSNPs in the urokinase-plasminogen activator (PLAU) gene with Alzheimer's disease and associated quantitative traits. Am J Med Genet B Neuropsychiatr Genet 144B:79-82
Sundar, Purnima Desai; Feingold, Eleanor; Minster, Ryan L et al. (2007) Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease. Neurobiol Aging 28:856-62
Kamboh, M I; Minster, R L; Feingold, E et al. (2006) Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures. Mol Psychiatry 11:273-9
Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas (2006) Lack of association of two chromosome 10q24 SNPs with Alzheimer's disease. Neurosci Lett 408:170-2

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