The genetic landscape of Alzheimer disease.
The genetic landscape of Alzheimer disease.
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DOI：
10.1016/b978-0-444-64076-5.00026-0
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发表时间：
2018-01-01
影响因子：
--
通讯作者：
Guerreiro, Rita
中科院分区：
文献类型：
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作者：
Carmona, Susana;Hardy, John;Guerreiro, Rita
阿尔茨海默病(AD)是一种进行性和神经退行性疾病，是最常见的痴呆形式，在老年人中发病率较高。在神经病理学上，这种疾病的定义是细胞外淀粉样β蛋白(Abeta)斑块和细胞内磷酸化tau蛋白的神经原纤维缠结。在遗传学上，第一个线索是由遗传连锁研究提供的，这些研究导致APP、PSEN1和PSEN2突变被确定为常染色体显性早发性AD的主要原因。另一个重要的标志是ApoEɛ4等位基因被确认为晚发性AD的危险因素。在过去的20年里，新的遗传和基因组技术的发展和实施使人们能够确定这种疾病中的其他遗传因素。全基因组关联研究确定了20多个具有共同变异的基因座，这些基因座对AD的易感性有很小的贡献。已知这些基因中的大多数与特定的生物途径有关：胆固醇代谢、免疫反应和内吞作用。最近，下一代测序(主要是全外显子组测序)的应用已经开始揭示具有中等效应的更罕见的变异对AD风险的贡献。这一领域的研究已经取得了长足的进步，取得了许多重要的成果，使人们能够更好地了解这种疾病。然而，要完全了解这种疾病的病因，还需要更多的努力，以便建立可靠的个体预测模型，并使我们更接近于开发治疗、预防或调节药物。
Alzheimer disease (AD), a progressive and neurodegenerative disease, is the most common form of dementia with high incidence in elderly people. Neuropathologically the disease is defined by the combined presence of extracellular amyloid-beta (Abeta) plaques and intracellular neurofibrillary tangles of phosphorylated tau protein. Genetically, the first clues were provided by genetic linkage studies that led to the identification of APP, PSEN1, and PSEN2 mutations as the main causes of autosomal-dominant early-onset AD. Another important hallmark was the identification of the APOE ɛ4 allele as a risk factor for late-onset AD. Over the last 20 years the development and implementation of new genetic and genomic technologies have allowed the identification of other genetic players in this disease. Genome-wide association studies identified more than 20 loci with common variability having small contributions to the susceptibility of AD. The majority of the genes mapped in these loci are known to be involved in specific biologic pathways: cholesterol metabolism, immune response, and endocytosis. More recently, the application of next-generation sequencing (mainly whole-exome sequencing) has begun to reveal the contribution of rarer variants with medium effects on risk for AD. This area of research has come a long way with many and important results allowing a better understanding of the disease. More efforts are still needed, however, to fully understand the etiology of this disease in order to establish reliable individual predictive models and put us closer to the development of a curative, preventive, or modulator drug.