CR1 is associated with amyloid plaque burden and age-related cognitive decline.
CR1 is associated with amyloid plaque burden and age-related cognitive decline.
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DOI：
10.1002/ana.22277
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发表时间：
2011-03
影响因子：
11.2
通讯作者：
De Jager, Philip L.
中科院分区：
文献类型：
--
作者：
Chibnik, Lori B.;Shulman, Joshua M.;Leurgans, Sue E.;Schneider, Julie A.;Wilson, Robert S.;Tran, Dong;Aubin, Cristin;Buchman, Aron S.;Heward, Christopher B.;Myers, Amanda J.;Hardy, John A.;Huentelman, Matthew J.;Corneveaux, Jason J.;Reiman, Eric M.;Evans, Denis A.;Bennett, David A.;De Jager, Philip L.
最近，全基因组关联研究已经确定了三个新的阿尔茨海默病(AD)易感基因：CLU、CR1和PICALM。我们利用来自两个队列研究的可用的神经心理学和尸检数据来调查这些基因座是否与认知功能减退和AD神经病理有关。宗教秩序研究(ROS)和快速记忆和老龄化项目(MAP)是一项纵向研究，招募了非痴呆症受试者，包括年度临床评估和死亡时的脑捐赠。我们评估了1666名受试者的CR1(Rs6656401)、CLU(Rs11136000)和PICALM(Rs7110631)。我们评估了基因分型和认知功能变化率以及AD相关病理改变之间的关系。最后，我们使用通径分析来确定SNPs和认知功能下降之间的关系是否通过AD病理来调节。在我们的研究队列中，ROS和MAP的平均随访年限分别为7.8年和4.3年。只有CR1基因与全球认知功能减退(p=0.011)和全球AD病理(p=0.025)相关。更具体地说，该基因座影响神经炎性淀粉样斑块的沉积(p=0.009)。在一项中介分析中，控制淀粉样蛋白病变强烈减弱了CR1基因座对认知功能下降的影响。我们发现CR1基因的共同变异对认知有广泛的影响，而且这种影响在很大程度上是由个体的淀粉样斑块负荷调节的。因此，我们强调了CR1易感等位基因的一个功能结果，并概括了该基因座在一般人群中对认知老化的作用。
Recently, genome-wide association studies have identified three new susceptibility loci for Alzheimer’s disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from two cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology. The Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) are longitudinal studies that enroll non-demented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000) and PICALM (rs7110631) in 1666 subjects. We evaluated associations between genotypes and rate of change in cognitive function as well as AD-related pathology. Lastly, we used pathway analysis to determine if relationships between SNPs and cognitive decline were mediated through AD pathology. Among our study cohort, the mean years of follow-up was 7.8 for ROS and 4.3 for MAP. Only the CR1 locus was associated with both global cognitive decline (p=0.011) and global AD pathology (p=0.025). More specifically, the locus affects the deposition of neuritic amyloid plaque (p=0.009). In a mediation analysis, controlling for amyloid pathology strongly attenuated the effect of the CR1 locus on cognitive decline. We found that common variation at the CR1 locus has a broad impact on cognition and that this effect is largely mediated by an individual’s amyloid plaque burden. We therefore highlight one functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population.
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影响因子：
3.3
作者：
Reitz, C.;Mayeux, R.
通讯作者：
Mayeux, R.
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
DOI：
10.1073/pnas.0900345106
发表时间：
2009-04-21
影响因子：
11.1
作者：
Reiman, Eric M.;Chen, Kewei;Caselli, Richard J.
通讯作者：
Caselli, Richard J.
影响因子：
9.9
作者：
Bennett, David A.;De Jager, Philip L.;Schneider, Julie A.
通讯作者：
Schneider, Julie A.
影响因子：
9.9
作者：
Bennett, DA;Schneider, JA;Wilson, RS
通讯作者：
Wilson, RS