The characteristic findings in Alzheimer's disease (AD) post-mortem brain (PMB) are degeneration of neuronstogether with extensive amounts of amyloid deposits (A 42) (a cleavage product of the amyloid precursorprotein encoded by the APP gene) and tau (encoded by the MAPT gene). Cerebrospinal fluid (CSF) A 42 andtau levels can predict AD but have a limited reliability in discriminating AD from other neurodegenerativediseases. The apolipoprotein (APOE) 4 allele and age are currently the only factors strongly associated withlate onset AD. The large gaps in our understanding of the genetic aspects of AD may include additional geneticfactors that impact age of onset and phenotypic expression of late onset AD. Individual genetic findings (non-synonomous SNPs) associated with complex diseases, such as AD, are unlikely to fully explain the substantialimpact of genetic variation on disease pathogenesis. Multilevel etiologic factors are likely to underlie complexdiseases and may include multiple loci within and surrounding a gene that influence regulation of transcriptionand post-transcription, emphasizing the need for integrative evaluation of large genetic regions andcorrelations with protein biomarker levels as a means for predicting disease risk. This proposal focuses on theoverall hypothesis that multiple genetic loci surrounding and within large gene regions act to regulate geneexpression in an AD specific manner. During the mentored phase (K99) of this investigation the first aim isto find multiple loci or combinations of SNPs (haplotypes) surrounding and within the APOE, APP and MAPTgenes that correlate with expression levels in CSF and PMB. Candidate genetic and protein biomarkers willexpand beyond APOE, APP and MAPT genes to include other genes likely to be biologically relevant toneurodegenerative disease.
The second aim i s to demonstrate that putative regulatory haplotypes functionallyimpact expression by utilizing genomic DNA, containing a particular putative regulatory haplotype, as the activesite of gene regulation in reporter and minigene assays. During the independent phase (R00), the final aim isto test regulatory haplotypes for their reliability in discerning between different AD phenotypes and between ADand other neurodegenerative diseases. Collectively, these proposed experiments are unique because they gobeyond the simple correlation between core promoter loci and biomarker expression levels by using acombination of genetic, statistical and functional techniques to evaluate the influence of multiple loci withinputative distant regulatory elements on AD relevant gene expression to find haplotypes that predict AD. Theresearch and career development components of this K99/R00 application will provide the necessary trainingfor the applicant to become a successful independent investigator who can integrate these techniques toimprove our understanding of neurodegenerative disease risk.

Public Health Relevance

Characterization of haplotype regulation of AD relevant expression levels (genetic predictors of biomarkers)may help find new targets for early intervention as well as translate into more accurate ways to predict andthus diagnose AD early in its progression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
7R00AG034214-05
Application #
8849625
Study Section
Special Emphasis Panel (NSS)
Program Officer
Miller, Marilyn
Project Start
2014-06-15
Project End
2015-07-31
Budget Start
2014-06-15
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$170,904
Indirect Cost
$63,078
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Bekris, L M; Khrestian, M; Dyne, E et al. (2018) Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease. J Neuroimmunol 319:19-27
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Bekris, Lynn M; Leverenz, James B (2015) The biomarker and therapeutic potential of miRNA in Alzheimer's disease. Neurodegener Dis Manag 5:61-74
Bekris, Lynn M; Tsuang, Debby W; Peskind, Elaine R et al. (2015) Cerebrospinal fluid A?42 levels and APP processing pathway genes in Parkinson's disease. Mov Disord 30:936-44
Millard, Steven P; Lutz, Franziska; Li, Ge et al. (2014) Association of cerebrospinal fluid A?42 with A2M gene in cognitively normal subjects. Neurobiol Aging 35:357-64
Bekris, Lynn M; Lutz, Franziska; Montine, Thomas J et al. (2013) MicroRNA in Alzheimer's disease: an exploratory study in brain, cerebrospinal fluid and plasma. Biomarkers 18:455-66
Li, Ge; Bekris, Lynn M; Leong, Lesley et al. (2013) TOMM40 intron 6 poly-T length, age at onset, and neuropathology of AD in individuals with APOE ?3/?3. Alzheimers Dement 9:554-61
Yu, Chang-En; Cudaback, Eiron; Foraker, Jessica et al. (2013) Epigenetic signature and enhancer activity of the human APOE gene. Hum Mol Genet 22:5036-47
Bekris, Lynn M; Lutz, Franziska; Yu, Chang-En (2012) Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE. J Hum Genet 57:18-25

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