Sequence variants of IDE are associated with the extent of β-amyloid deposition in the Alzheimer's disease brain

被引:42
作者
Blomqvist, MEL
Chalmers, K
Andreasen, N
Bogdanovic, N
Wilcock, GK
Cairns, NJ
Feuk, L
Brookes, AJ
Love, S
Blennow, K
Kehoe, PG
Prince, JA [1 ]
机构
[1] Karolinska Inst, Ctr Genome & Bioinformat, Stockholm, Sweden
[2] Univ Bristol, Dept Clin Sci Care Elderly, Frenchay Hosp, Bristol, Avon, England
[3] Huddinge Univ Hosp, Dept Geriatr Med, Neurotec, Stockholm, Sweden
[4] Huddinge Univ Hosp, Dept Clin Neurosci Occupat Therapy & Elderly Care, Div Geriatr Med B84, S-14186 Huddinge, Sweden
[5] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
[6] Hosp Sick Children, Ctr Appl Genome, Toronto, ON M5G 1X8, Canada
[7] Univ Bristol, Frenchay Hosp, Inst Clin Neurosci, Dept Neuropathol, Bristol, Avon, England
[8] Univ Gothenburg, Sahlgrens Univ Hosp, Dept Clin Neurosci & Transfus Med, Gothenburg, Sweden
关键词
IDE; linkage disequilibrium; Alzheimer's disease; beta-amyloid;
D O I
10.1016/j.neurobiolaging.2004.07.011
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Insulin degrading enzyme, encoded by IDE, plays a primary role in the degradation of amyloid P-protein (A beta), the deposition of which in senile plaques is one of the defining hallmarks of Alzheimer's disease (AD). We recently identified haplotypes in a broad linkage disequilibrium (LD) block encompassing IDE that associate with several AD-related quantitative traits. Here, by examining 32 polymorphic markers extending across IDE and testing quantitative measures of plaque density and cognitive function in three independent Swedish AD samples, we have refined the probable position of pathogenic sequences to a 3' region of IDE, with local maximum effects in the proximity of marker rs 1887922. To replicate these findings, a subset of variants were examined against measures of brain A beta load in an independent English AD sample, whereby maximum effects were again observed for rs1887922. For both Swedish and English autopsy materials, variation at rs1887922 explained approximately 10% of the total variance in the respective histopathology traits. However, across all clinical materials studied to date, this variant site does not appear to associate directly with disease, suggesting that IDE may affect AD severity rather than risk. Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients. (c) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:795 / 802
页数:8
相关论文
共 35 条
[1]   Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease [J].
Abraham, R ;
Myers, A ;
Wavrant-DeVrieze, F ;
Hamshere, ML ;
Thomas, HV ;
Marshall, H ;
Compton, D ;
Spurlock, G ;
Turic, D ;
Hoogendoorn, B ;
Kwon, KM ;
Petersen, RC ;
Tangalos, E ;
Norton, J ;
Morris, JC ;
Bullock, R ;
Liolitsa, S ;
Lovestone, S ;
Hardy, J ;
Goate, A ;
O'Donovan, M ;
Williams, J ;
Owen, MJ ;
Jones, L .
HUMAN GENETICS, 2001, 109 (06) :646-652
[2]   HISTOPATHOLOGICAL CRITERIA FOR PROGRESSIVE DEMENTIA DISORDERS - CLINICAL-PATHOLOGICAL CORRELATION AND CLASSIFICATION BY MULTIVARIATE DATA-ANALYSIS [J].
ALAFUZOFF, I ;
IQBAL, K ;
FRIDEN, H ;
ADOLFSSON, R ;
WINBLAD, B .
ACTA NEUROPATHOLOGICA, 1987, 74 (03) :209-225
[3]   Evidence for genetic linkage of Alzheimer's disease to chromosome 10q [J].
Bertram, L ;
Blacker, D ;
Mullin, K ;
Keeney, D ;
Jones, J ;
Basu, S ;
Yhu, S ;
McInnis, MG ;
Go, RCP ;
Vekrellis, K ;
Selkoe, DJ ;
Saunders, AJ ;
Tanzi, RE .
SCIENCE, 2000, 290 (5500) :2302-+
[4]   Polymorphisms of insulin degrading enzyme gene are not associated with Alzheimer's disease [J].
Boussaha, M ;
Hannequin, D ;
Verpillat, P ;
Brice, A ;
Frebourg, T ;
Campion, D .
NEUROSCIENCE LETTERS, 2002, 329 (01) :121-123
[5]   Early-onset autosomal dominant Alzheimer disease: Prevalence, genetic heterogeneity, and mutation spectrum [J].
Campion, D ;
Dumanchin, C ;
Hannequin, D ;
Dubois, B ;
Belliard, S ;
Puel, M ;
Thomas-Anterion, C ;
Michon, A ;
Martin, C ;
Charbonnier, F ;
Raux, G ;
Camuzat, A ;
Penet, C ;
Mesnage, V ;
Martinez, M ;
Clerget-Darpoux, F ;
Brice, A ;
Frebourg, T .
AMERICAN JOURNAL OF HUMAN GENETICS, 1999, 65 (03) :664-670
[6]   APOE ε4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Aβ protein [J].
Chalmers, K ;
Wilcock, GK ;
Love, S .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2003, 29 (03) :231-238
[7]   Degradation of the Alzheimer's amyloid β peptide by endothelin-converting enzyme [J].
Eckman, EA ;
Reed, DK ;
Eckman, CB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (27) :24540-24548
[8]   Insulin-degrading enzyme rapidly removes the β-amyloid precursor protein intracellular domain (AICD) [J].
Edbauer, D ;
Willem, M ;
Lammich, S ;
Steiner, H ;
Haass, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (16) :13389-13393
[9]   Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Aβ42 levels and risk for Alzheimer disease [J].
Ertekin-Taner, N ;
Allen, M ;
Fadale, D ;
Scanlin, L ;
Younkin, L ;
Petersen, RC ;
Graff-Radford, N ;
Younkin, SG .
HUMAN MUTATION, 2004, 23 (04) :334-342
[10]   Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees [J].
Ertekin-Taner, N ;
Graff-Radford, N ;
Younkin, LH ;
Eckman, C ;
Baker, M ;
Adamson, J ;
Ronald, J ;
Blangero, J ;
Hutton, M ;
Younkin, SG .
SCIENCE, 2000, 290 (5500) :2303-+