This is a resubmission of our competing renewal application to continue a highly productive study previously funded for three years as an IRPG. The study has been led by Dr Rudolph Tanzi at Mass General Hospital in collaboration with co-investigators at the U Alabama and Johns Hopkins U These investigators worked together since 1989 to ascertain, evaluate, and follow the NIMH Genetics Initiative Alzheimer's disease (AD) sample, which currently includes 1527 individuals in 457 families, the largest uniformly ascertained and evaluated sample assembled for the study of AD genetics The IRPG was aimed at analyzing and performing preliminary follow up of a high-resolution genome screen of the NIMH sample. Having substantially completed the original aims, the IRPG has been dissolved and we are applying for funds to identify novel AD genes within linkage peaks identified in the genome screen, using a positional candidate approach, augmented by linkage disequilibrium mapping In addition to the expected highly significant linkage peak on chromosome 19q (at the APOE locus), our screen yielded several regions with evidence of """"""""suggestive"""""""" linkage to AD. In accord with the reviewers' suggestion, the follow up studies in our revised application focus on the two highest-priority confirmed AD linkage regions on chromosomes 9 and 10, where we and other groups have observed consistent evidence for linkage. We plan to refine these linkage regions using highly polymorphic markers in linkage and family-based association analyses. We will then test clusters of tightly spaced single nucleotide polymorphisms (SNPs) for association with AD, initially in compelling and then in plausible candidate genes. Putative AD genes will also be tested in an independent sample assembled for association analyses, the Consortium on Alzheimer's Genetics (CAG) sample. If the initial candidate gene approach does not lead to the disease loci, we will continue by analyzing SNP clusters in genes not previously considered AD candidates, and - if necessary - in intergenic regions. Any SNPs found to be strongly associated with AD will be phenotypically and functionally characterized using a variety of statistical and experimental methods. Only as time and funds permit, we will employ the same general approach to follow up other loci that meet criteria for 'suggestive' linkage. While we have devised a strategy that integrates the best available methods to identify genes involved in a complex disease like AD, we realize that the field is evolving rapidly. Thus, as the study progresses we will routinely adjust our methods to take advantage of advances in methodology. ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Mammalian Genetics Study Section (MGN)
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Lehner, Thomas
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Massachusetts General Hospital
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Gamberger, Dragan; Lavra?, Nada; Srivatsa, Shantanu et al. (2017) Identification of clusters of rapid and slow decliners among subjects at risk for Alzheimer's disease. Sci Rep 7:6763
Bettayeb, Karima; Hooli, Basaraj V; Parrado, Antonio R et al. (2016) Relevance of the COPI complex for Alzheimer's disease progression in vivo. Proc Natl Acad Sci U S A 113:5418-23
Herold, C; Hooli, B V; Mullin, K et al. (2016) Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3. Mol Psychiatry 21:1608-1612
Bettayeb, Karima; Chang, Jerry C; Luo, Wenjie et al. (2016) ?-COP modulates A? peptide formation via retrograde trafficking of APP. Proc Natl Acad Sci U S A 113:5412-7
Choi, Se Hoon; Kim, Young Hye; Quinti, Luisa et al. (2016) 3D culture models of Alzheimer's disease: a road map to a ""cure-in-a-dish"". Mol Neurodegener 11:75
Alfonso, Stephanie I; Callender, Julia A; Hooli, Basavaraj et al. (2016) Gain-of-function mutations in protein kinase C? (PKC?) may promote synaptic defects in Alzheimer's disease. Sci Signal 9:ra47
Kim, Young Hye; Choi, Se Hoon; D'Avanzo, Carla et al. (2015) A 3D human neural cell culture system for modeling Alzheimer's disease. Nat Protoc 10:985-1006
D'Avanzo, Carla; Aronson, Jenna; Kim, Young Hye et al. (2015) Alzheimer's in 3D culture: challenges and perspectives. Bioessays 37:1139-48
Weissmiller, April M; Natera-Naranjo, Orlangie; Reyna, Sol M et al. (2015) A ?-secretase inhibitor, but not a ?-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP. PLoS One 10:e0118379
Liu, Qing; Waltz, Shannon; Woodruff, Grace et al. (2014) Effect of potent ?-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol 71:1481-9

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