Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Ann Neurol. 2011 Mar;69(3):560-9. doi: 10.1002/ana.22277. Epub 2011 Mar 9.
Recently, genome-wide association studies have identified 3 new susceptibility loci for Alzheimer's disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from 2 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 nondemented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000), and PICALM (rs7110631) in 1,666 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 whether relationships between single nucleotide polymorphisms and cognitive decline are mediated through AD pathology.
Among our study cohort, the mean years of follow-up were 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 1 functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population.
最近，全基因组关联研究确定了 3 个新的阿尔茨海默病（AD）易感性位点：CLU、CR1 和 PICALM。我们利用来自 2 项队列研究的可用神经心理学和尸检数据，来研究这些位点是否与认知能力下降和 AD 神经病理学相关。
宗教秩序研究（ROS）和拉什记忆与衰老项目（MAP）是纵向研究，纳入了无痴呆的受试者，包括每年的临床评估和死亡时的大脑捐献。我们评估了 1666 名受试者的 CR1（rs6656401）、CLU（rs11136000）和 PICALM（rs7110631）。我们评估了基因型与认知功能变化率以及 AD 相关病理学之间的关联。最后，我们使用途径分析来确定单核苷酸多态性与认知能力下降之间的关系是否通过 AD 病理学来介导。
在我们的研究队列中，ROS 的平均随访年限为 7.8 年，MAP 的平均随访年限为 4.3 年。只有 CR1 位点与整体认知能力下降（p=0.011）和整体 AD 病理学（p=0.025）都相关。更具体地说，该位点影响神经纤维状淀粉样斑块的沉积（p=0.009）。在中介分析中，控制淀粉样蛋白病理学强烈减弱了 CR1 位点对认知能力下降的影响。
我们发现 CR1 位点的常见变异对认知能力有广泛影响，而这种影响在很大程度上是由个体的淀粉样斑块负担介导的。因此，我们强调了 CR1 易感等位基因的 1 种功能后果，并将该位点的作用推广到一般人群的认知衰老。
