The search for rare variants in Alzheimer’s disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful. Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs. Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aβ pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions. Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs.

中文翻译：

---

接受挑战：揭示罕见遗传变异在阿尔茨海默病中的作用

寻找阿尔茨海默病（AD）的罕见变异通常被认为是高风险高回报的情况。与这一努力相关的挑战是真实的。尽管如此，全基因组技术在大量病例和对照或小型、特征明确的家庭中的应用已开始取得成果。与 AD 相关的罕见变异已被证明会增加风险或导致疾病，但也能预防 AD 的发展。所有这些都可能成为新药开发的目标。多项独立研究现已表明 NOTCH3、TREM2、SORL1、ABCA7、BIN1、CLU、NCK2、AKAP9、UNC5C、PLCG2 和 ABI3 中的罕见变异与 AD 存在关联，并表明它们可能通过多种机制影响疾病。这些基因已报告在免疫系统、脂质代谢、突触可塑性和细胞凋亡中的功能。然而，从含有与 AD 相关的罕见变异的基因集合中出现的主要途径是 Aβ 途径。还提出了数十种其他基因中罕见变异的关联，但尚未在独立研究中得到重复。复制此类研究结果是研究 AD 等复杂疾病的罕见变异所面临的挑战之一。在这篇评论中，我们讨论了其中一些主要挑战以及可能的解决方案。综合方法、大型数据集和数据库的可用性以及新分析方法的开发将继续产生具有影响 AD 的罕见变异的新基因。未来，更广泛、更多样化的遗传学研究，以及对具有深入特征的家族的研究，将增强我们对疾病发病机制的理解，使我们走上成功药物开发的正确道路。