Ringman John M, Coppola Giovanni
Easton Center for Alzheimer’s Disease Research at UCLA, 10911 Weyburn Ave, #200, Los Angeles, CA 90095-7226, USA.
Continuum (Minneap Minn). 2013 Apr;19(2 Dementia):358-71. doi: 10.1212/01.CON.0000429179.21977.a1.
This article discusses the current status of knowledge regarding the genetic basis of Alzheimer disease (AD) with a focus on clinically relevant aspects.
The genetic architecture of AD is complex, as it includes multiple susceptibility genes and likely nongenetic factors. Rare but highly penetrant autosomal dominant mutations explain a small minority of the cases but have allowed tremendous advances in understanding disease pathogenesis. The identification of a strong genetic risk factor, APOE, reshaped the field and introduced the notion of genetic risk for AD. More recently, large-scale genome-wide association studies are adding to the picture a number of common variants with very small effect sizes. Large-scale resequencing studies are expected to identify additional risk factors, including rare susceptibility variants and structural variation.
Genetic assessment is currently of limited utility in clinical practice because of the low frequency (Mendelian mutations) or small effect size (common risk factors) of the currently known susceptibility genes. However, genetic studies are identifying with confidence a number of novel risk genes, and this will further our understanding of disease biology and possibly the identification of therapeutic targets.
本文讨论了阿尔茨海默病（AD）遗传基础的当前知识状况，重点关注临床相关方面。
AD的遗传结构很复杂，因为它包括多个易感基因以及可能的非遗传因素。罕见但高度显性的常染色体显性突变解释了一小部分病例，但在理解疾病发病机制方面取得了巨大进展。一个强大的遗传风险因素APOE的发现重塑了该领域，并引入了AD遗传风险的概念。最近，大规模全基因组关联研究正在为这幅图景增添许多效应大小非常小的常见变异。大规模重测序研究有望识别出更多风险因素，包括罕见的易感变异和结构变异。
由于目前已知的易感基因频率低（孟德尔突变）或效应大小小（常见风险因素），遗传评估目前在临床实践中的作用有限。然而，遗传研究正在确定许多新的风险基因，这将加深我们对疾病生物学的理解，并可能有助于确定治疗靶点。
