This proposal is a continuation of our grant to delineate the genetics of Alzheimer disease [AD], the most common form of dementia after age 40. Within the past five years, four AD genes have been described. APP, PS-I and II are autosomal dominant causative loci in early (<60) familial AD but represent <2% of all AD cases. The vast majority of cases are late- onset familial or sporadic AD. Through the present grant, the laboratories of Drs. Pericak-Vance and Haines were the first to describe the increased risk related to the APOE-4 allele and the protective effect of the APOE-2 allele. By all estimations, APOE accounts for approximately 50% of the total predicted genetic effect and is the single most important biological risk factor yet identified in AD. Although this finding has dramatically changed the focus of AD research, another 50% of genetic etiology of AD remains unexplained. In addition to delineating the APOE effect, we have completed a genome screen using our initial set of extended late-onset pedigrees and have identified several regions deserving more scrutiny. We have now expanded our data set from 52 to 200+ multiplex late-onset AD families (250+ sampled affected sibpairs) and have 500+ sporadic AD patients and 300+ spouse controls. We also have identified the genetically isolated Indiana Amish population who, despite having a lower prevalence of AD and a decreased frequency of APOE-4, maintain familial aggregation. The above resources permit a more detailed and sophisticated genome screening and analyses to identify all major and moderate genetic effects in AD, something not possible even three years ago. We will use newly described sibpair and affected- relative-pair analyses in conjunction with lod score analysis to make greatest use of the screening data. We will also examine gene/gene interactions between the regions we (or others) conform as harboring AD genes. The ultimate goal of our proposal is the identification of all major loci involved in AD, the first step in combating this devastating neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS031153-08S2
Application #
6353848
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Murphy, Diane
Project Start
1997-02-20
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
8
Fiscal Year
2000
Total Cost
$50,000
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Beecham, Gary W; Martin, Eden R; Gilbert, John R et al. (2010) APOE is not associated with Alzheimer disease: a cautionary tale of genotype imputation. Ann Hum Genet 74:189-94
Naj, Adam C; Beecham, Gary W; Martin, Eden R et al. (2010) Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet 6:e1001130
Lambert, Jean-Charles; Sleegers, Kristel; González-Pérez, Antonio et al. (2010) The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study. J Alzheimers Dis 22:247-55
Beecham, Gary W; Naj, Adam C; Gilbert, John R et al. (2010) PCDH11X variation is not associated with late-onset Alzheimer disease susceptibility. Psychiatr Genet 20:321-4
Beecham, Gary W; Martin, Eden R; Li, Yi-Ju et al. (2009) Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet 84:35-43
Slifer, Michael A; Martin, Eden R; Gilbert, John R et al. (2009) Resolving the relationship between ApolipoproteinE and depression. Neurosci Lett 455:116-9
Beecham, Gary W; Schnetz-Boutaud, Nathalie; Haines, Jonathan L et al. (2009) CALHM1 polymorphism is not associated with late-onset Alzheimer disease. Ann Hum Genet 73:379-81
Xu, Pu-Ting; Li, Yi-Ju; Qin, Xue-Jun et al. (2007) A SAGE study of apolipoprotein E3/3, E3/4 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease. Mol Cell Neurosci 36:313-31
Xu, Pu-Ting; Li, Yi-Ju; Qin, Xue-Jun et al. (2006) Differences in apolipoprotein E3/3 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease. Neurobiol Dis 21:256-75
Ercoli, Linda; Siddarth, Prabha; Huang, Sung-Cheng et al. (2006) Perceived loss of memory ability and cerebral metabolic decline in persons with the apolipoprotein E-IV genetic risk for Alzheimer disease. Arch Gen Psychiatry 63:442-8

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