Rongve Arvid, Årsland Dag, Graff Caroline
Seksjon for alderspsykiatri, Klinikk for psykisk helsevern, Helse-Fonna, Haugesund, Norway.
Tidsskr Nor Laegeforen. 2013 Aug 6;133(14):1449-52. doi: 10.4045/tidsskr.12.0873.
Alzheimer's disease is the most frequent cause of dementia. Recent knowledge reveals several new risk genes. We wish to summarise the knowledge of genetic factors related to Alzheimer's disease.
This article is based on findings in Alzgene, a database that summarises genetic association studies in Alzheimer's disease, a literature search in PubMed and the authors' own experience in dementia research.
Several mutations of the genes APP, PSEN1 and PSEN2 are described. These cause around half of all cases of the rare early onset autosomal dominant form of Alzheimer's disease. Heritability, or how much of the development of the disease in an individual that is explained by genetics, is between 60 and 80% in the most common late onset form of Alzheimer's disease. APOE ε4 is the most robust risk gene for the development of this form of the disease, but recently ten new genes that increase the risk of developing Alzheimer's disease were identified by applying genome-wide association studies. These genes code for proteins that are central in the metabolism of cholesterol, activation of the immune system and synaptic cell membrane processes.
New hypotheses on the disease mechanisms for Alzheimer's disease are suggested based on the identification of new risk genes. These hypotheses partly replace and partly supplement the previously dominant amyloid pathway hypothesis. The new risk genes point to the potential for new biomarkers for specific disease processes and to possible new targets for future disease modifying therapies.
阿尔茨海默病是痴呆最常见的病因。最近的研究发现了几个新的风险基因。我们希望总结与阿尔茨海默病相关的遗传因素知识。
本文基于阿尔茨基因数据库（该数据库总结了阿尔茨海默病的遗传关联研究）的研究结果、在PubMed上的文献检索以及作者自身在痴呆研究方面的经验。
描述了APP、PSEN1和PSEN2基因的几种突变。这些突变导致了约一半的罕见早发性常染色体显性阿尔茨海默病病例。在最常见的晚发性阿尔茨海默病中，遗传度（即个体疾病发展中由遗传因素解释的比例）在60%至80%之间。APOEε4是这种疾病发展中最有力的风险基因，但最近通过全基因组关联研究确定了另外十个增加患阿尔茨海默病风险的基因。这些基因编码的蛋白质在胆固醇代谢、免疫系统激活和突触细胞膜过程中起核心作用。
基于新风险基因的发现提出了关于阿尔茨海默病发病机制的新假说。这些假说部分取代并部分补充了先前占主导地位的淀粉样蛋白途径假说。新的风险基因指出了针对特定疾病过程的新生物标志物的潜力以及未来疾病修饰疗法可能的新靶点。
