Reitz Christiane, Mayeux Richard
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Ann N Y Acad Sci. 2009 Oct;1180:75-96. doi: 10.1111/j.1749-6632.2009.04945.x.
Late-onset Alzheimer's disease (LOAD) is the most common cause of late-onset dementia in western societies. Despite remarkable achievements in human genetics throughout the years, in particular technological advances in gene mapping and in statistical methods that relate genetic variants to disease, to date only a small proportion of the genetic contribution to LOAD can be explained leaving several remaining genetic risk factors to be identified. A possible explanation for the difficulty in gene identification is that LOAD is a multifactorial complex disorder with both genetic and environmental components. Multiple genes with small effects each ("quantitative trait loci"[QTLs]) are likely to contribute to the quantitative traits associated with the disease, such as memory performance, amyloid/tau pathology, or hippocampal atrophy. The motivation for identifying the genetics of LOAD is clear. Not only could it shed light on disease pathogenesis, but it may also provide potential targets for effective treatment, screening, and prevention. Here, we review the usefulness of genetic variation as diagnostic tools and biomarkers in LOAD and discuss the potentials and difficulties researchers face in designing appropriate studies for gene discovery.
迟发性阿尔茨海默病（LOAD）是西方社会迟发性痴呆最常见的病因。尽管多年来人类遗传学取得了显著成就，特别是在基因定位以及将基因变异与疾病相关联的统计方法方面的技术进步，但迄今为止，LOAD的遗传因素中只有一小部分能够得到解释，仍有若干遗传风险因素有待确定。基因识别困难的一个可能解释是，LOAD是一种具有遗传和环境成分的多因素复杂疾病。多个具有微小效应的基因（“数量性状位点”[QTLs]）可能对与该疾病相关的数量性状有贡献，如记忆表现、淀粉样蛋白/ tau病理或海马萎缩。识别LOAD遗传学的动机很明确。它不仅可以阐明疾病发病机制，还可能为有效治疗、筛查和预防提供潜在靶点。在此，我们综述了遗传变异作为LOAD诊断工具和生物标志物的有用性，并讨论了研究人员在设计合适的基因发现研究时所面临的潜力和困难。
